EXCHANGE 


BOBl'lZWMVd 


37  1922 
UNIVERSITY  OF  PENNSYLVANIA 


THE 

METHYLATION  OF  PARA-AMINOPHENOL 
BY  MEANS  OF  FORMALDEHYDE 


BY 

ERNEST  CARL  WAGNER 


A  THESIS 


PRESENTED  TO  THE  FACULTY  OF  THE  GRADUATE  SCHOOL 
IN  PARTIAL  FULFILLMENT  OF  THE  REQUIRE- 
MENTS FOR  THE  DEGREE  OF 
DOCTOR  OF  PHILOSOPHY 


1921 


UNIVERSITY  OF  PENNSYLVANIA 


THE 

METHYLATION  OF  PARA-AMINOPHENOL 
BY  MEANS  OF  FORMALDEHYDE 


BY 

ERNEST  CARL  WAGNER 


A  THESIS 


PRESENTED  TO  THE  FACULTY  OF  THE  GRADUATE  SCHOOL 
IN  PARTIAL  FULFILLMENT  OF  THE  REQUIRE- 
MENTS FOR  THE  DEGREE  OF 
DOCTOR  OF  PHILOSOPHY 


1921 


ACKNOWLEDGMENT 


The  subject  of  this  study  was  suggested 
by  Dr.  W.  T.  Taggart,  under  whose  super- 
vision and  with  whose  encouragement  the 
work  described  was  undertaken. 

Much  practical  help  and  many  useful  sug- 
gestions were  given  by  Dr.  H.  S.  Lukens. 

To  these  gentlemen  the  writer  takes  this 
opportunity  to  express  his  appreciation. 


The  Methylation  of  p-Aminophenol 
by  Means  of  Formaldehyde 

A  Study  of  Certain  Methods  for  the  Conversion 
of  the  Condensation-products  of  Formaldehyde 
and  p-Aminophenol  into  N-Methyl-p-aminophenol 

This  paper  it  divided  as  follows: 

/-  The  Condensations  of  Formaldehyde  and 
Aromatic  Amines 

A.  Condensations  in  Neutral  or  Alkaline  Media 

B.  Condensations  in  Acid  Media 

C.  Summary  of  Important  Condensations  and 

Secondary  Reactions 

//-  Methylation  of  Aromatic  Amines  by  Means 
of  Formaldehyde 

III-  Experimental  Results  on  the  Methylation  of 
p-Aminophenol  by  Means  of  Formaldehyde 

IV-  Summary 


I.     The  Condensations  of  Formaldehyde  and  Aromatic  Amines 

In  the  condensations  of  formaldehyde  with  the  amines,  the 
fundamental  change  consists  in  the  splitting  out  of  the  elements 
of  water,  with  the  result  that  a  methylene-group  is  introduced. 
Typically  the  necessary  hydrogen  atoms  are  displaced  from  an 
amino-group,  or  from  two  imino-groups.  It  is  characteristic  of 
certain  condensations,  however,  that  only  nuclear  hydrogen 
atoms  are  involved.  The  course  of  the  condensation  depends 
upon  (a)  the  nature  of  the  medium  in  which  condensation  oc- 
curs, i.e.,  whether  neutral,  alkaline,  or  acid,  (b)  the  relative  pro- 
portions of  amine  and  aldehyde,  (c)  the  presence  of  substances 
with  which  further  reaction  may  occur,  and  (d)  the  influence  of 
substituent  groups  present  in  the  amine  molecule. 


METHYI<ATION  OF  PARA-AMINOPHENOI, 

With  respect  to  these  influences,  it  can  be  said  introductorily 
that  what  may  be  termed  the  normal  condensation  occurs  in 
neutral  or  alkaline  solution,  that  which  results  in  presence  of 
acid  being  essentially  different.  The  relative  amounts  of  amine 
and  aldehyde  present  determine  whether  one  or  two  amine  mole- 
cules will  be  involved  in  the  condensation,  and  also,  when  an 
excess  of  amine-salt  is  present,  whether  or  not  further  condensa- 
tions of  the  primary  product  with  uncondensed  amine  will  occur. 

The  influence  of  substituent  groups  upon  aldehyde  condensa- 
tions was  observed  by  Kibner1  who  found  that  trichloraniline 
did  not  react  with  chloral,  though  less  chlorinated  anilines  con- 
densed. In  other  cases,  such  as  o-dimethyltoluidine,  a  condens- 
ing agent  (zinc  chloride)  may  be  required.2  It  has  been  found 
also  that  tribromaniline  does  not  condense  with  formaldehyde, 
either  under  ordinary  conditions,  or  in  a  sealed  tube  at  250°. 
The  effect  of  the  substituent  bromine-atoms  in  this  case  is  so 
strong  that  the  action  of  an  excess  of  bromine  upon  a  benzol 
solution  of  anhydroformaldehydeaniline  not  only  brominates  the 
aromatic  nucleus,  but  to  a  certain  extent  eliminates  the  methyl- 
ene-group  previously  united  with  the  nitrogen-atom.  This  is 
evidenced  by  the  appearance  of  tribromaniline  as  a  constant  pro- 
duct of  this  bromination. 

A  —  Condensations   of  Formaldehyde    and  Aromatic  Amines   in 
Neutral  or  Alkaline  Media. 

The  essential  reactions  which  may  occur,  depending  upon  the 
nature  of  the  amine,  and  upon  the  relative  proportions  of  amine 
and  formaldehyde,  are  the  following  : 

(a)  C6H6.N|H2T6|CH2  =  C6H6.N:CH2   +    H7O 

(  anhyd  rof  ormaniline  ) 


, 
C6H6NH!H 


(methylene-di-phenamine  base) 

C'    >  N 


R>  NH 

$&**&  ______  i 

(tnethylene-di-phenamine  base) 
1  Annal.,  302,  349. 
'Alexander,  Ber.,  25,  2408  (1892). 


MKTHYLATION  OF  PARA-AMINOPHENOI, 

Compounds  of  these  types  are  more  or  less  generally  referred 
to  as  "SchifFs  Bases,"  which  include  also  the  condensation- 
products  of  other  aldehydes. 

The  earliest  known  and  simplest  formaldehyde  condensation 
of  type  (a)  among  aromatic  amines  was  studied  by  Pratesi  and 
Tollens3  in  the  case  of  aniline.  Anhydroformaldehydeaniline, 
or  anhydroformaniline,  is  thus  obtained  in  the  trimeric  form 
(C6H5N.CH2)3.4  Polymerization  occurs  also  with  other  amines, 
such  as  the  toluidines5  and  p-aminophenol.6  The  existence  of  two 
forms  of  such  compounds,  having  different  melting  points  and 
solubilities,  has  been  observed  in  several  cases.  This  was  attributed 
at  first  to  different  degrees  of  polymerization.  It  was  shown  by 
Bischoff,  however,  that  (CH3.C6H4.N.CH,)n  exists  in  two  forms, 
both  of  which  have  the  same  molecular  weight,  corresponding  to 
the  formula  (CH3.C6H4.N.CH2)3.  He  concluded  that  the  two 
forms  must  be  geometrical  isomers  of  the  cis  and  trans  types  with 
respect  to  the  CH3.C6H4-groups  attached  to  the  [— N.CH2-]3 
ring.  Anhydroformaniline  likewise  probably  exists  in  two  forms. 
Dimeric  forms  of  these  anhydro-bases,  such  as 

(CH3.C6H4.N.CH2)2, 

or  structurally,    CH3.C6H4.N<£^2>N.C«H4.CHS, 

have  been  reported.7 

The  general  reaction  of  which  the  formaldehyde-aniline  con- 
densation serves  as  a  type  was  soon  applied  to  the  toluidines,  etc., 
by  Wellington  and  Tollens,8  and  has  since  that  time  been  extended, 
where  applicable,  to  apparently  all  amines  of  importance,  both 
aliphatic  and  aromatic,  as  well  as  to  many  heterocyclic  compounds. 

3  Pratesi,  Gazz.  chint.  ital.,  14,  351  (1884);  Tollens,  Ber.,  17,  653  (1884); 
18,3309(1885). 

*  Miller  and  PlochU,   Ber.y   25,  2020,  (1892);  Bischoff,  Ber.,  3!,  3248 
(1899). 

6  Bischoff.  /.  c. 

•  D.  R.  P.,  68707. 

7  Ber.y  31,  2037,  3248;  AnnaL,  256,  288. 

8  Bcr.,  18,3298(1885). 


F  PARA-AMINOPHENOI, 

Condensation  of  two  equivalents  of  amine  and  one  of  formalde- 
hyde is  of  type  (b),  and  yields  methylene-di-imine  compounds  of 
the  type-formula  Ar.NH.CH2.NH.Ar.  Thus  two  molecules  of 
aniline  and  one  of  formaldehyde  form  methylenediphenyldi-imine, 
or  dianilinomethane  :8  C6H5.NH.CH2.NH.C6H5.  By  boiling  this 
compound  in  alcohol,  it  is  transformed  into  anhydroformaniline.10 
Exactly  analogous  condensations  occur  with  other  amines.11 

The  most  interesting  reaction  of  the  di-imine  bases  occurs  when 
they  are  heated  with  amine-salts.  Diamino-diphenylmethane 
derivatives  are  thus  formed,  by  a  rearrangement  which  recalls  the 
transformation  of  hydrazobenzene  to  benzidine  :12 

Ar.NH.CH2NH.Ar.  *»->  Ar.NH.CH2.Ar.NH2 

•H*  NH2.Ar.CH2.Ar.NH2. 

As  these  compounds  are  formed  directly  when  condensation  is 
conducted  in  presence  of  free  acid,  and  with  base  in  excess  of 
formaldehyde,  the  secondary  reaction  just  given  belongs  more 
properly  to  Section  B,  where  its  probable  mechanism  will  be 
indicated. 

Condensations  of  types  (a)  and  (b)  may  occur  simultaneously, 
one  or  the  other  predominating;  excess  of  aldehyde  favors  the 
first,  while  excess  of  amine  favors  the  second.13 

Condensations  of  type  (c)  are  characteristic  of  secondary 
amines,  and  are  in  no  essential  manner  different  from  the  pre- 
ceding. The  methyltoluidines,  for  example,  condense  with 
formaldehyde  to  form  (C7H7.N.CH3)2CH2.14  When  heated  with 
amine-salts,  these  compounds,  like  those  obtained  from  primary 
amines,  are  rearranged  to  form  dialkylamino-diphenylmethane 
derivatives. 

Compounds  intermediate  between  the  methylene-di-imine 
bases  (Ar.NH.CH2NH.Ar.),  and  the  diamino-diphenylmethanes 

9  Pratesi,  Bischoff,  /.  c. 

10  Eberhardt  and  Welter,  Ber.,  27,  1804  (1894). 

11  Eibner,  Annal.,  302,  349  (1898):  Bischoff,  /.  c.\  Bischoff  and  Reinfeld, 
Ber.,  36,  41  (1903);  D.  R.  P.  138393,  etc. 

12  D.  R.  P.  63081,  107718. 

13  Eibner;  Eberhardt  and  Welter,  /.  c. 

14  Braun,  Ber.,  41,  2145  (I9°8). 


METHYIyATlON  OF  PARA-AMINOPHENOI, 

(NH2.Ar.CH2.Ar.NH2),  viz.,  the  aminobenzylanilines  (NH2.Ar.- 
CH2.NH.Ar.),  are  formed  when  an  anhydro  formaldehyde-base  is 
heated  with  an  amine-salt  :15 

C6H5.N:CH2  +  H.C6H4.NHa(HCl)~- 

C6H5.NH.CH3.C6H4.NH,(HC1). 

Condensations  of  nuclear-substituted  amines  proceed  often  in 
the    normal    manner;      o-nitraniline,      for      example,      yields 


Similar  condensations  occur  with  halogenated  amines,  aminoben- 
zoic  acids,  aminosulphonic  acids,  benzidine,  tolidine,  phenetidine, 
etc. 

It  is  of  great  practical  importance  that  the  methylene-group  of 
the  diphenylmethane  compounds  can  be  condensed  with  a  third 
amine-molecule  by  oxidation,  forming  triphenylmethane  deriva- 
tives, among  which  fuchsine  and  the  homologous  pararosanilines 
are  included.17 

Primary  condensation-products  of  the  type  Ar.N  :CH2,  although 
probably  cyclic  polymers  devoid  of  double  bonds,  are  able  to  unite, 
by  addition,  with  several  substances,  the  most  important  of  which 
are  (i)  hydrogen,  (2)  sulphurous  acid  or  bisulphites,  and  (3) 
hydrocyanic  acid.  These  additions  occur  according  to  the  follow- 
ing equations  :18 

(1)  Ar.N:CH2    -f  2H      .=    Ar.NH.CH3 

(2)  Ar.N:CH2    +    NaHSO3    =    Ar.NH.CH2SO3Na 

(3)  Ar.N:CH2    +       HCN      =    Ar.NH.CH2.CN 

The  bisulphite  compound  contains  a  replaceable  —  SO3H  or 
-SO3Na  group  :19  by  interaction  with  cyanide  a  phenylglycineni- 
trile  results: 

Ar.NH.CH2.SO,Na  +  NaCN  =  Ar.NH.CH2.CN  +  Na2SO3. 
The  synthesis  of  phenylglycine  and  its  homologues  is  thus  possible 

»  D.  R.  P.  87934- 

16  Pulvermacher,  Ber,,  25,  2764526,  955. 

17  D.  R.  P.  53937,  55565,  61146,  67013,  73092. 

18  Miller  and  Plochl,  Ber.,  25,  2020   (1892);   Eibner,   AnnaL,   3x6,   89 
(1901);  Lcpetit,  Atti.  accad.  Lincei,  26,  I,  126  (1917);  Gazz.  chitn.  ital.,  47, 
I,  197  (1917);  C.  A.,  1918,  366. 

19  Knoevenagel,  Ber.,  37,  4073  (1904). 


PARA-AMINOPHENOI, 


by  a  convenient  method,  as  the  products  may  be  obtained  directly 
by  proper  treatment  of  amine,  cyanide,  formaldehyde,  and  alkali.20 

Preparation  of  phenylglycine-o-carbonic  acid  is  accomplished  by 
a  similar  process,  starting  with  anthranilic  acid.21  Condensations 
of  formaldehyde  with  anthranilic  acid  or  its  esters  have  been 
rather  carefully  studied.22 

Union  of  the  anhydro-base  Ar.N  :CH2  with  hydrocyanic  acid  or 
bisulphite  may  take  place  either  after  isolation  of  the  base,  or  in  a 
mixture  of  amine,  formaldehyde,  and  cyanide  or  bisulphite.  In 
the  latter  case  it  is  to  be  supposed  that  the  cyanhydrin  or  aldehyde- 
bisulphite  is  primarily  formed,  and  reacts  with  the  amine  : 


iOH  +  HiN.H.Ar 
CH20  +  HCN  -*  CH3< 


•—  Ar.  NH.CH2.  CN  -f-  H2O 
CH,0  +  NaHS03  -~  CHa<j^--±--II-iNH-Ar 

w  v^ojlN  3, 

—  *Ar.NH.CHa.SO3Na  +  H,O. 

The  corresponding  bisulphite  compound  of  p-aminophenol  is 
HO.C6H4.NH.CH2.SO3Na.  It  may  be  made  either  by  dissolving 
the  condensation-product  HO.C6H4.N  :CH2  in  bisulphite  solu- 
tion,23 or  by  dissolving  p-aminophenol  in  formaldehyde-  bisulphite 
solution.  The  addition-product  readily  evolves  sulphur  dioxide 
when  heated  with  acids,  and  may  therefore  be  represented  as  a 
loose  compound  of  the  formula  (HO.C6H4N  :CH2)  NaHSO3.  Its 
alkaline  solution  exhibits  reducing  properties,  and  it  has  been 
recommended  as  a  photographic  developer  under  the  name 
"Eurekin."  The  general  similarity  of  this  compound  and  the 
developer  "Metol,"  as  shown  by  the  formulas 

20  JBer.,  27,  1805;  39,  987;  D.  R.  P.  135332,  145376,  etc. 
31  D.  R.  P.  117924,  120105,  158090,  151538. 

22  Erdmann,  /•/*'•  Ch.,  (2),  68,387,   569;  Mehner,  ib.,  (2),  63,  244565, 
533J  Goldschmidt,  Chem.  Ztg.,  26,   179;   Haller  and  Fiesselmann,  Annal., 
324,  n8;  Bischoff  and  Reinfeld,  Ber.,  35,  3440;  36,  41. 

23  D.  R.  P.  68707. 


METHYI.ATION  OF  PARA-AMINOPHENOI, 

(p-HO.C6H4N:CH2)NaHS03,      (p-HO.C6H4.NH.CH3)2H2SO4, 

(Eurekin)  (Metol) 

seems  to  be  of  little  significance  in  the  preparation  of  the  latter. 

B — Condensations  of  Formaldehyde  and  Aromatic  Amines  in 

Acid  Media." 

The  condensation  of  aniline  and  formaldehyde  in  presence  of 
hydrochloric  acid  yields  a  chlorinated  product  C6H5.NH.CH2C1.25 
This  compound  is  itself  of  no  great  importance,  but  derives 
interest  from  the  fact  that  it  readily  loses  a  molecule  of  hydro- 
chloric acid,  especially  in  contact  with  alkalies,  and  passes  into 
the  anhydride  of  p-aminobenzyl  alcohol : 


NHjHHiCl     -f    !  OiCH,         NH. 


CH2- 


(exochlormethyl-  (anhydroamino- 

aniline)  benzylalcohol) 

These  reactions  occur  strikingly  in  the  case  of  methylaniline,28 
the  exochlormethyl-derivative  of  which  separates  as  white  needles 
when  the  secondary  base  is  allowed  to  stand  with  formaldehyde 
in  dilute  hydrochloric  acid  solution.  The  product,  when  treated, 
in  solution,  with  alkali,  is  transformed  into  white,  amorphous 
anhydro-p-methylamino-benzylalcohol.  Analogous  reactions  occur 
also  with  ethylaniline27  and  other  primary  and  secondary  amines. 
That  anhydroaminobenzylalcohol  is  a  para-compound  is  shown  by 
its  reduction  to  p-toluidine.28  The  anhydroaminobenzylalcohols 
are  characterized  by  their  insolubility  in  water  and  in  the  usual 

24  D.  R.  P.  53937,   70402,  95184,  95600,    96851,  96852,  97710;    Ber.,     31, 
1037    (1891));   33,250(1901);    C.  C.,  1898,  11,159;    1912,  II,  2070;  1906,  I, 
1416;  C.  A.,  11,  582  (1917.) 

25  Goldschmidt,  Chem.  Ztg.,  a4,  284  (1900);  D.  R.  P.  96851;  cf.  Raikow, 
Chem.  Ztg.,  20,  307  (1896). 

26  Goldschmidt,  /.  c. 

31  Goldschmidt,  Chem.  Ztg.,  26,  606,  (1902). 
18  D.  R.  P.  83544. 


METHYI,ATION  01?  PARA-AMINOPHENOI, 

organic  solvents ;  they  are  soluble  in  dilute  hydrochloric  or  other 
mineral  acid,  with  formation  of  the  corresponding  salt.  The 
anhydro-alcohols  derived  from  primary  amines  are  themselves 
secondary  amines,  and  form  nitrosamines.  The  anhydroamino- 
benzylalcohols  are  obtained  in  more  or  less  polymerized  condition, 
the  degree  of  polymerization  varying  with  the  amount  of  acid 
present  during  their  formation.29  The  simplest  member  is 
obtained  in  polymerized  form  from  the  true  alcohol, 
NH2.C6H4.CH2OH,  by  heating  with  acid,30  as  well  as  by  treatment 
of  exochlormethylanilme,  C6H5.NH.CH2C1,  with  alkali. 

The  anhydroaminobenzylalcohols  may  be  prepared  also  from 
condensation-products  of  the  types  Ar.N  :CH2  and  (Ar.NH)2CH, 
by  action  of  strong  acids.  Thus  anhydroformaniline,  in  contact 
with  strong  hydrochloric  acid,  is  gradually  transformed  into  exo- 
chlormethylaniline,  which  is  converted  by  alkali  to  anhydro-p- 
aminobenzylalcohol.31  By  action  of  glacial  acetic  acid  in  the  cold, 
however,  an  isomeric  form  of  anhydroformaniline  results,  having 
the  probable  formula  C6H5NH.CH2C6H4.N  :CH2,32  and  possessing 
the  ability  for  further  condensations. 

Typical  condensations  occur  with  /3-phenylhydroxylamine,88 
and  with  p-substituted  amines  such  as  p-toluidine,  xylidenes, 
and  p-chloraniline.34  The  products  resemble  the  other  anhydro- 
aminoalcohols ;  that  from  p-chloraniline  is  exceptional  in  being 
crystallizable.  In  the  same  way  p-aminophenol  yields  an 
amorphous  base  of  the  probable  formula,35 

NH 
HO.C6H,<  I 

CH2 

This  differs  from  the  anhydroaminobenzylalcohols  mentioned 
above  by  its  solubility  in  alkalies  as  the  phenolate;  it  is  precipi- 
tated from  acid  solution  by  sodium  carbonate. 

«D.  R.  P.  96851. 

90  D.  R.  P.  83544. 

11  D.  R.  P.  95184. 

M  D.  R.  P.  121506. 

M  D.  R.  P.  87972. 

84  D.  R.  P.  122474. 

K  Orloff,  "Formaldehyde,"  Leipzig,  (1909)  p.  95. 

8 


METHYLATION  OF  PARA-AMINOPHENOL 

With  salts  of  aromatic  amines,  the  anhydroaminobenzylalcohols 
combine  to  form  diphenylmethane  derivatives,  a  reaction  of 
importance  :38 


H.C6H4.NH,(HC1) 
CH, 


By  use  of  nuclear-substituted  and  N-alkylated  amines,  unsym- 
metrically  substituted  diphenylmethane  derivatives  may  be 
obtained. 

It  will  be  recalled  that  diphenylmethane  derivatives  are  formed 
(page  4)  in  another  way,  by  heating  the  methylenedi-imine  bases 
with  excess  of  amine-salt,  or  with  amine  and  acid,  a  transforma- 
tion like  that  of  hydrazobenzene  to  benzidine  : 
Ar.NH.CH2.NH.Ar.  «->  Ar.NH.CH2.Ar.NH2 

-w  NH2.Ar.CH2.Ar.NH2. 

This  transformation  has  been  studied  for  o-nitraniline  by  Meyer 
and  Rohmer,37  and  for  several  secondary  amines  by  Braun.38 
It  appears  that  the  exochlor-compound  is  first  formed,  with 
splitting-off  of  a  molecule  of  amine.  The  former  may  then  pass 
into  the  anhydroaminobenzylalcohol,  reaction  of  which  with  the 
amine  first  liberated  yields  the  diphenylmethane  compound  which 
constitutes  the  end-product.  For  the  simplest  case  the  trans- 
formation may  be  indicated  by  the  scheme  : 


C6H5NH  CHCD  C6H5.NH.CH2.C1—  C6H4 

C6H5NH>C±1«      —*       C6H5.NH,.HC1  ---  „  —  '       CH, 


This  general  process  is  susceptible  of  many  modifications.  It  is 
most  simply  carried  out  in  a  single  operation,  by  interaction  of 
formaldehyde  and  excess  of  amine  in  presence  of  acid.  When 
mixed  products  are  desired,  the  di-imine  is  first  produced,  and  is 
further  condensed  with  the  salt  of  another  amine. 

w  D.  R.  P.  96762. 

nBer.t  33,  250  (1901). 

88  Ber.,  4x,  2145  (1908.) 


M3THYLATION  OF  PARA-AMINOPH£NOI< 

The  same  products  may  be  obtained  in  still  another  way,  from 
the  p-aminobenzylaniline  derivatives,  NH2.Ar.CH2.NH.Ar,39 
which  are  formed  by  interaction  of  amine-salts  with  bases  of  the 
type  Ar.N  :CH2  (pages  4  and  5).  The  p-amino-benzylaniline  thus 
obtained,  when  heated  with  amine  and  hydrochloric  acid,  yields  a 
diphenylmethane  derivative,  with  elimination  of  a  molecule  of 
amine : 

NH2.C6H4.CH2.NH.C6H5  +  H.C6H4.NH2(HC1)  —* 

NH2.C6H4.CH2.C6H4.NH2(HC1)   +  C6H5.NH2. 

The  anhydroaminobenzyl  (or  homologous)  alcohols  show  a 
characteristic  reaction  with  /?-arylhydroxylamines,  by  which 
result  the  p-amino-benzaldehydes : 

NH 
C6H5.NHOH  +    I       >C6H,~  C6H5.N:CH.C6H4.NHa 

CH2 

(H20) 

^   C6H5.NH2  +  OHC.C6H4.NH2. 

The  same  products  are  obtained  by  suitable  reduction  of  nitro- 
compounds  in  neutral  solution  and  in  presence  of  formaldehyde. 

While  the  secondary  amines  condense  with  formaldehyde  in  the 
normal  manner,  by  virtue  of  the  presence  of  amino-hydrogen,  the 
tertiary  amines  show  a  different  behavior.  Dimethylaniline,  con- 
densed with  formaldehyde  in  acetic  acid  solution,  yields  tetra- 
methyldiaminodiphenylmethane, 

(CH3)2N.C6H4.CH2.C6H4.N(CH3)2.40 

The  m-aminophenols,  and  the  corresponding  cresols,  react  in  the 
same  way.41  By  dehydration  and  oxidation,  the  products  of  such 
condensations  yield  the  pyronines.42 

The  m-diamines  condense  similarly  to  form  diphenylmethane 
derivatives,  from  which  acridine  compounds  are  obtainable  by  loss 
of  ammonia  and  by  oxidation.43  The  o-diamines  yield  imidazole 
compounds.44 

39  D.  R.  P.  87934,  104230,  105797,  108064,  109498. 

40  Mohlau  and  Heinze,   Ber.,  35,  359  (1902);   cf.  Pinnoff,  Ber.,  27,  3166 
(1894). 

41  D.  R.  P.  Anm.,  5528;  D.  R.  P.  58955,  75373;  Ber.,  27,  1894  (1894);  /. 
pr.  Ch,,  54,  217  (1896). 

42  D.  R.  P.  59003,  63081,  75138,  84988,  99613- 

"Orloff,  "Formaldehyde,"  Leipzig,  1909,  pp.  97,  115-123,  gives  a  general 
account,  together  with  some  of  the  numerous  patents. 
44  O.  Fischer,  Per.,  25,  2711;  32,  245. 

10 


METHYIvATlON  OF  PARA-AMINOPHENOI, 

Amines  of  the  naphthalene  series  condense  with  formaldehyde 
in  acid  solution  with  elimination  of  ammonia  and  water.  Double 
junction  between  two  naphthalene  nuclei  at  their  a  and  ft  positions 
is  effected  through  a  -CH2-  and  an  -NH-  group.  When. 
however,  the  /^-position  is  occupied,  as  by  -SO3H,  the  amino- 
group  is  not  involved,  but  the  two  nuclei  are  united  through 
-CH2-  attached  at  the  4-positions.45 

It  will  not  be  profitable  to  extend  further  the  list  of  condensa- 
tions, though  it  is  not  even  approximately  complete.  A  brief  and 
fairly  comprehensive  survey  of  the  subject  (up  to  about  1908)  is 
given  by  Orloff.46  Later  work  is  recorded  in  the  academic  and 
patent  literature. 

C — Summary  of  Important  Condensations  of  Formaldehyde 
and  Aromatic  Amines*' 

(i)     Primary  Condensations 

(a)  In  absence  of  acids,  one  molecule  of  formaldehyde 
and  one  molecule  of  primary  amine  react  to  form 
readily  polymerized  N-methylene-amines  (anhydro- 
formaldehydeamines)  : 

Ar.N:H2"    o!CH2  »-»  Ar.N  :CH2  +  H2O 

(b)  In  absence  of  acids,  one  molecule  of  formaldehyde 
and  two  molecules  of  primary  or  secondary  amine 
react  to  form  methylene-di-imino  bases  (methylene- 
diphenamines,  dianilinomethanes") : 


Ar.NHiH  Ar.NH 

Ar.NHiH  U;LH*  ~~*  Ar.NH>Li1' 


Ar 


R>N;H 

^>NJH 


Ar 


R>N\ 
O  CH,  •—    £        ^CU,  +  H,O 


Ar 


(c)     Tertiary  amines  condense  to  form  diphenylmethane 

derivatives : 

"Morgan,    Proc.,  16,  131;  i95,  132  (1897);  /.  C.  5.,  77,   814;  73,  536; 
Reed,  /.  pr.  Ch.,  35,  298;  Bucherer  and  Seide,  Ber.t  40,  859;  Senier  and 
Austin,/.  C.  S.,  QI,  1233;  D.  R.  P.  84379. 
46  /.  c.  pp.  81-123. 
*7  Cf.  Friedlander,  V.  p.  5. 

II 


METHYLATION  OF  PARA-AMINOPH^NOI, 


R,N.Ar.iH    , 

R2N.Ar.JH  ;; 

(d)  In  presence  of  acids,  one  molecule  of  amine  and 
one  of  formaldehyde  unite  to  form  (in  the  case  of 
HC1)  the  exochlormethylamino-compounds,  which 
are  converted  by  loss  of  hydrochloric  acid  into  the 
reactive  anhydroaminobenzyl  alcohols.  These  are 
para-compounds,  unless  the  para-position  is  initially 
occupied,  in  which  case  analogous  compounds  result 
with  the  -CH2-  group  otherwise  disposed  : 


Ar.NH:ILH:Cl  +    :  O!CH2 

-HCI  NH 

Ar.NH.CHaCl  •—  Ar<  I 

CH2 

(2)     Secondary  Condensations 

(a)  The  anhydro  formaldehyde-amines  unite  with  amine- 

salts    in    the    cold    to    form    p-aminobenzylaniline 
derivatives  : 
Ar.N:CH2  -f  H.Ar.NH2(HCl)  *»-+ 

Ar.NH.CH2.Ar.NH2(HCl). 

(b)  The  p-aminobenzylanilines  unite  with  amine-salts  in 

acid  medium,  and  at  higher  temperatures,  forming 
diphenylmethane  derivatives,  with  elimination  of  a 
molecule  of  amine: 
Ar.NH.CH2.Ar.NH2  m  ^  Ar.NH, 
NH2.Ar.H.  NH2.Ar.CH2.Ar.NH2 

(c)  The    methylenedi-imine  bases,    when   heated    with 
amine-salts,     pass     into     corresponding     diphenyl- 
methane derivatives  by  rearrangement  : 
Ar.NH.CH2.NH.Ar.  **-* 

NH2.Ar.CH2.NH.Ar    *H»  NH2.Ar.CH2.Ar.NH2. 

(d)  The  anhydroaminobenzylalcohols  react  with  amine 
salts  to  form  diphenylmethane  derivatives: 


-f  H.A 
CH, 

NH 


12 


OF  PARA-AMINOPHENOI, 

II.     Methylation  of  Aromatic  Amines  by  Means  of  Formaldehyde 

Among  the  aromatic  amines,  the  time-honored  method  of 
alkylation  employs  the  alkyl  halides.  Much  more  convenient 
than  this  method,  however,  is  that  in  which  an  alkyl  sulphate,  and 
especially  methyl  sulphate,  is  the  active  agent.48  This  method  is 
coming  into  increasingly  wide  use,  because  of  the  activity  of 
methyl  sulphate,  and  because  of  the  relative  simplicity  of  the  oper- 
ations. The  methylation  of  p-aminophenol  to  N-methyl-p-amino- 
phenol  may  be  accomplished  by  this  means,  which  is  probably  that 
by  which  the  process  is  now  conducted  commercially.  Methylation 
may  be  effected  similarly  by  the  use  of  the  methyl  ester  of 
p-toluene-sulphonic  acid.49 

Other  methods  for  conversion  of  primary  to  secondary  amines 
include  the  following  : 

(1)  Action  of  methyl  alcohol  in  presence  of  concentrated 
sulphuric  acid.50 

(2)  Hydrogenation  of  Schiff's  bases  catalytically,  in  presence 
of  nickel51  or  metallic  oxides.62 

(3)  Alkylation    of    primary    to    secondary   amines    through 
action  of  alkyl  iodides  upon  SchifFs  bases.83    This  method 
involves  intermediate  formation  of  unstable  quaternary 
compounds  by  addition  of  alkyl  iodides  to  bases  of  the 
type  R.N:CHR'.     The  quaternary  salts,  by  hydrolysis, 
yield  secondary  amine  and  aldehyde  : 

R.N:CHR'  +  R"I— 


HSO  R>NH  -f  CHO.R'  +  HI 

^Ullman,  Annal.,  327,  164  (1903);  Meldola  and  Hallely,  /.  C.  S., 
I9I2T,  912;  Werner,/.  C.S.,  105,  2762  (1914);  Havasand  Guyot,  Chem.  Ztg., 
37,  812;  Shepard,  /.  A.  C.  S.,  38,  2507  (1916);  Klemenc  and  Edhoffcr, 
Monats.,  38,  553  (1918.) 

49  Ullmann  and  Wenner,  Annal.,    327,  120  (1903);  Weyl,  "Method**," 
//,  1269  (1911.) 

50  D.  R.  P.  288825. 

61  Maihle,  Bull.  Soc.  chim.,  25,  321  (1919). 

M  E.  P.  124219. 

M  Decker  and  Becker,  Annal.,  395,  362. 

13 


METHYI,ATION  OF  PARA-AMINOPHENOI, 

Among  the  secondary  amines  prepared  by  this  method  are 
methyl-  and  ethyl-aniline  from  benzylidine-aniline,  and 
methyl-p-toluidine  from  benzylidine-p-toluidine. 
(4)  Condensation  of  primary  amine  and  phenol.54  N-methyl- 
p-aminophenol  may  be  prepared  in  this  way  from  hydro- 
quinone  and  methylamine : 

HO.C6H4.iOH"TNH;H.CH3  ^ 

"    HO.C6H4.NH.CHS  +  H2O 

A  somewhat  similar  method  involves  the  interaction  of 
p-chlor-phenol  and  methylamine:55 

HO.C6H4.;CTT~HT  NH.CH3— 

HO.C6H4.NH.CH3  +  HC1 

These  methods  are  more  properly  described  as  arylations 
of  aliphatic  amines  than  as  alkylations  of  aromatic 
amines,  though  this  distinction  has  no  significance  so  far 
as  concerns  the  products. 

Consideration  of  the  several  primary  condensation-products 
of  formaldehyde  and  the  aromatic  amines  suggests  four  ways 
in  which  the  introduced  methylene-group  might  be  changed  to 
a  methyl-group : 

1 I )  Hydrogenation  of  the  anhydro formaldehyde-amines  : 

Ar.N  :CH2  +  2H  **->  Ar.NH.CH3 

(2)  Reduction    of  the    exochlormethyl-amines    obtained     by 
condensation  in  acid  solution: 

Ar.NH.CH2Cl  +  2H  *»•>  Ar.NH.CH3  +  HC1 

(3)  Reduction  of  the  bisulphite  addition-products  of  the  an- 
hydro formaldehyde-amines  : 

Ar.NH.CH2.SO3Na  +  2H  »-»  Ar.NH.CH3  +  NaHSO3 

(4)  Hydrolysis  of  the    hydrocyanic    acid    addition-products 
of  the  anhydroformaldehyde-amines,  and  elimination  of 
carbon  dioxide  by  heat : 

Ar.NH.CH2.CN  «M>  Ar.NH.CH2.COOH 

*»-*  Ar.NH.CH3  +  CO2. 

64  D.  R.  P.  260234-  Harger,/.  A.  C.  S.,  41,  270  (1919). 
66  D.  R.  P.  205415. 


METHYXATION  OF  PARA-AMINOPH3NOI, 

A  brief  discussion  of  methods  hitherto  applied  for  reactions 
such  as  the  foregoing  will  be  given  first,  and  will  be  followed  by 
a  description  of  experiments  on  the  methylation  of  p-aminophe- 
nol  by  these  methods.  This  reaction  was  chosen  because  it  ap- 
pears that  the  indicated  methylation  has  not  been  effected  by 
the  above  methods  (except  the  last),  and  because  the  product, 
N-methyl-p-aminophenol,  is  a  compound  of  considerable  interest, 
its  sulphate  being  the  photographic  developer  known  as  "Metol." 

(i)  Hydrogenation  of  the  Anhydroformaldehyde-bases,  i.  e., 
of  the  Group  -N:  CH- 

The  methods  by  which  this  reduction  has  been  accomplished 
include  the  following : 

(a)  Reduction  by  Sodium-amalgam,  or  by  Sodium,  and  Ab- 
solute Alcohol — 

These  two  methods  constitute  classic  means  for  effecting  this 
hydrogenation.56  Fischer,  avoiding  the  use  of  acids  because  of 
their  decomposing  effect  upon  the  -N:CH-  group,  used  the 
above  agents  for  reductions  such  as  that  of  benzylidene-aniline 
to  benzylaniline.  As  is  well  known,  the  intensity  of  the  reduction 
may  be  modified  by  use  of  different  alcohols.57  Attempts  to  re- 
duce the  compound  HO.C6H4.N  :CH2  by  these  means  met  with 
no  success. 

(b)  Reduction  by  Means  of  Zinc-dust  and  Alkali — 

This  method  is  the  subject  of  several  patents,  dealing  with  the 
production  of  secondary  from  primary  amines.58  The  alkylation 
or  arylation  is  best  carried  out  by  interaction  of  amine  and  alde- 
hyde in  presence  of  excess  of  reducing  agent;  the  medium  for 
the  reaction  is  water,  alcohol  (or  acetic  acid,  but  not  strong 
acids.)59  These  methods  do  not  seem  to  have  come  into  general 
use,  and  are  probably  not  highly  efficient:  several  attempted 
methylations  of  aniline  gave  only  small  yields  of  methylaniline. 

The  reduction  of  benzylidine-p-aminophenol  by  means  of  zinc- 

56  O.  Fischer,  Ber.,  19,  748  (1886);  Annal.,  241,  328  (1887);  245,  279 
(1888);  Miller  and  Plochl,  Ber.,  25,  2020  (1892). 

57  See,  e.  g.,  Miller  and  Plochl,  /.  c. 

M  D.  R.  P.  75854,  105345;  Prudhomme,  Bull.  soc.  chim.,  23,  69  (1905), 
59  E.  P.  102834,  A.  P.  1221077; /.  C.  S.,  115,  198. 

15 


ME)THYI,ATION  OF  PARA-AMINOPHENOI, 

dust  and  sodium  hydroxide,  on  the  other  hand,  takes  place  without 
difficulty,60  giving  good  yields  of  benzyl-p-aminophenol.  In 
view  of  this  fact,  it  is  interesting  to  record  that  methylene-p- 
aminophenol  resisted  all  efforts  at  reduction  by  the  same  process. 

(c)  Reduction  by  Zinc  in  Acid  Medium — 

Miller  and  Plochl61  showed  that  anhydro formaldehyde-aniline 
can  be  reduced  to  methylaniline  by  hydrochloric  acid  and  zinc- 
dust.  Goldschmidt62  carried  out  the  same  reduction  with  tin  and 
hydrochloric  acid.  No  yields  are  stated  for  these  reductions. 

By  reduction  of  methyl ene-p- aminophenol  with  zinc-dust  and 
acid,  a  partial  conversion  to  N-methyl-p-aminophenol  was  ob- 
tained, as  will  appear  in  the  experimental  part  (section  III). 

(d)  Reduction  Electrolytically  in  Alkaline  Medium — 

By  this  method  Brand  and  Honig63  obtained  benzylmethylamine 
and  benzyl-p-aminophenol  by  the  normal  course  of  the  reduction, 
and  o-aminophenol  and  toluene  from  benzal-o-aminophenol.  The 
writer  was  able  to  reduce  benzylidine-p-aminophenol  in  this  way, 
but  methylene-p-aminophenol  was  not  hydrogenated. 

(e)  Reduction  Electrolytically  in  Acid  Solution — 
Reduction  under  these  conditions  suffers  the  disadvantage  that 

the  operation  of  necessity  extends  over  a  considerable  period  of 
time,  during  which  certain  changes  incident  to  the  contact  of  the 
condensation-product  and  acid  are  in  progress.  It  is  therefore 
thought  necessary  to  maintain  a  low  temperature  so  long  as  acid 
and  condensation-product  are  in  contact.  According  to  a  recom- 
mended procedure,64  the  condensation-product  is  dissolved  in  50 
per  cent  sulphuric  acid  at  -12,°  and  electrolysis  is  conducted  at 
or  below  o°,  using  a  cathode  of  lead,  copper,  nickel,  or  mercury. 
In  this  way  both  aliphatic  and  aromatic  amines  may  be  alkylated 
or  arylated. 

Numerous  reductions  of  methylene-p-aminophenol  by  a  simi- 
lar process  were  carried  out,  using  generally  40  per  cent  sul- 

60  D.  R.  p.  211869, 

61  /.  c. 

62  Chem.  Ztg.,  28,  1229  (1904). 

63  Zeit.  electroch.,  18,  745. 

64  D.  R.  P.  143197. 

16 


METHYLATION  OF  PARA-AMINOPHENOI, 

phuric  acid  and  a  cathode  of  lead.  Certain  of  the  trials  were 
partially  successful,  while  others,  intended  to  be  identical,  were 
attended,  so  far  as  could  be  observed,  and  for  reasons  which  were 
not  discovered,  by  no  absorption  of  hydrogen,  and  by  the  forma- 
tion of  no  detectable  secondary  amine.  The  process  showed  no 
uniform  improvement  when  conducted  at  low  temperature. 

(f)  Electrolytic  Reduction  of  Nitro-compounds  in  Presence 
of  Formaldehyde — 

Lob65  and  Goecke86  carried  out  reductions  of  nitrotoluene  in 
hydrochloric  acid-alcohol  solution,  with  a  lead  cathode,  and  in 
presence  of  an  excess  of  formaldehyde.  From  p-nitrotoluene 
there  were  obtained  dimethyl-p-totuidine  (about  40  per  cent),  and 
another  compound,  called  by  Lob  dimethylditoluidine,  and  by 
Goecke  trimethylenetritoluidine  (but  which,  it  would  appear, 
was  probably  an  anhydroaminobenzyl  alcohol). 

This  process  was  applied  to  p-nitrophenol,  both  in  presence  of 
one  equivalent  of  formaldehyde,  and  of  an  excess.  In  neither 
case  could  any  mono-methyl-derivative  be  isolated,  though  some 
dimethyl-p-aminophenol  was  obtained;  under  the  first-mentioned 
conditions  some  p-aminophenol  resulted  by  simple  reduction  of 
p-nitrophenol.  Similar  reduction  of  p-nitrosophenol  in  presence 
of  formaldehyde  likewise  failed  to  produce  secondary  amine. 

(g)  Reduction  by  Sodium  Hydrosulphite — 

The  applicability  of  sodium  hydrosulphite  for  reduction  of 
methylene-amines  might  appear  a  priori  improbable  in  view  of 
the  readiness  with  which  these  compounds  unite  by  addition  with 
sulphurous  acid  or  bisulphites;  as  commercial  sodium  hydrosul- 
phite always  reeks  with  sulphur  dioxide,  the  immediate  forma- 
tion of  the  addition-product  Ar.NH.CH2.SO3H  seems  probable. 
Reduction  of  such  compounds  to  Ar.NH.CH3  by  hydrosulphite 
could  hardly  be  expected. 

Attempted  reductions  of  methyl ene-p-aminophenol  by  means 
of  sodium  hydrosulphite  yielded  no  secondary  amine,  but  a  readily 
soluble  yellow-white  crystalline  substance  which  evolved  sulphur 
dioxide  when  warmed  with  acids. 
65  Zeit.  eleciroch.,  4,  428  (1897/8). 
«Ib.,  9,470  (1903)- 

17 


METHYIvATlON  OF  PARA-AMINOPHENOI, 

(2)  Reduction  of  the  Exochlormethylanilines,  formed  by 
Acid  Condensation — 

Only  a  single  intance  has  been  found  in  which  such  a  reduction 
is  reported.  Goldschmidt67  reduced  N-methyleneaniline  (an- 
hydroformaniline)  with  tin  and  hydrochloric  acid,  condensed 
the  resulting  methylaniline  with  formaldehyde,  and  then  reduced 

the  resulting  C6H5.N<;;J?*   .  with  tin  and  hydrochloric    acid, 
v~xl,L,l 

obtaining  dimethylaniline. 

A  prolonged  attempt  to  duplicate  the  second  reduction,  using 
tin  and  hydrochloric  acid  at  ioo,°  was  without  effect  upon  the 
exochlor-compound.  Similar  experiments  were  carried  out 
with  p-amino-phenol,  which  was  condensed  with  formaldehyde 
in  presence  of  hydrochloric  or  sulphuric  acid  in  varying  amounts. 
The  product  was  subjected  to  reduction  by  various  means,  but 
in  no  case  could  the  presence  of  secondary  amine  be  detected. 
(5)  Reduction  of  the  Bisulphite  Addition-products  of  the 

Anhydro  formaldehyde-bases — 

As  a  means  for  testing  the  possibility  of  effecting  the  change 
Ar.NH.CH2.SO3H  «-»  Ar.NH.CH3  +  HSO3Na,  the  bisulphite 
addition-product  of  methyleneaniline  was  prepared  from  formal- 
dehyde-bisulphite and  aniline,68  and  was  reduced  by  tin  or  zinc 
and  hydrochloric  acid.    In  both  cases  free  sulphur  was  separated, 
but  steam-distillation  of  the  alkalized  liquid  yielded  no  volatile 
product.    The  possibility  of  splitting  off  the  -SO3H  group  hydro- 
lytically  was  also  studied,  but  positive  results  were  not  obtained. 
(4)     Hydrolysis    of    the    Hydrocyanic    Acid    Addition-pro- 
ducts of  the  Anhydr of ormaldehy de-Bases,  and  Elimina- 
tion of  Carbon  Dioxide  by  Heat — 

The  decarboxylation  of  p-hydroxy-phenyglycine  was  suggested 
by  Paul69  as  a  method  for  preparation  of  methyl-p-aminophenol. 
Trial  of  this  method  by  Harger70  gave  poor  results,  and  led  him 
to  a  further  study  of  the  method  of  Merck  and  Co.,  using  hydro- 
87  Chent.  Ztg.,  28,  1229  (1904). 
68  Orloff,  /.  £.,  p.  37. 
*  Zeit.  angcw.  Ch.  10,  17  (1897). 
70 /.  A.  <T.  S.,  41,  270  (1919). 

iS 


METHYLAT1ON  OF  PARA-AMINOPHENOL 

quinone  and  methylamine.71     The  writer  made  no  trial  of  Paul's 
method. 

III.    Experimental  Results  on  the  Methy lation  of  p-Aminophenol 
by  Means  of  Formaldehyde. 

Results  by  methods  (2)  and  (3)  (see  page  14)  will  be  given 
briefly  first.  Method  (4)  was  not  subjected  to  trial,  and  need 
not  be  referred  to  again.  Method  (i),  on  which  numerous  ex- 
periments were  made,  will  be  considered  last. 

Reduction  of  Exochlormethyl-p-aminophenol, 

HO.C6H4.NH.CH2Cl— 

According  to  the  general  reaction  given  on  page  12  (d),  p- 
aminophenol  would  react  with  formaldehyde  in  hydrochloric  acid 
solution  as  follows : 


HO.C6H4.NH;H.  HjCl  +  :  O  ;CH,  — 

HO.C6H4.NH.CH1C1  +  HO. 
( exochlormethy  1-p-aminophenol ) 

The  condensation-product  loses  hydrochloric  acid  under  the  in- 
fluence of  alkali  (sodium  carbonate),  and  is  converted  into 

NH 

hydroxy-anhydro-aminobenzylalcohol,    HO.C6H3<  i      »      which 

CH2 

is  insoluble  in  water.  The  instability  of  the  exochlor-compound 
in  presence  of  alkali  must  be  borne  in  mind  in  selecting  a  method 
for  its  reduction.  Alkaline  reduction  is  excluded,  as  the  an- 
hydrobenzylalcohol-derivative  would  form  at  once,  and  on  reduc- 
tion would  yield  an  oxytoluidine.72  Acid  reduction,  after  the 
anhydroaminobenzylalcohol  is  once  formed,  is  also  inadmissible, 
as  this  compound,  when  dissolved  in  dilute  acids,  does  not  re- 
vert to  the  exochlor-compound,  but,  by  virtue  of  its  character  as 
a  secondary  amine,  forms  a  salt. 

For  the  preparation  of  exochlormethyl-p-aminophenol,  recourse 
was  had  to  the  method  of  Goldschmidt,73  and  to  several  patented 

71  D.  R.  P.  260234;  A.  P.  1297685  (Harger). 

"  D.  R.  P.  83544. 

™  Chtm.  Ztg.,  24,  284  (1900). 

19 


METHYIvATlON  OF  PARA-AMINOPHENOI, 

processes.74  The  last-mentioned  patent  deals  with  the  condensa- 
tion of  formaldehyde  with  para-substituted  aromatic  bases  (not 
p-aminophenol),  and  seems  therefore  to  be  especially  relevant, 
though  it  is  the  alkali  transformation-products  of  the  exochlor- 
compounds  the  preparation  of  which  is  there  described.  The 
exochlor-compounds  formed  remain  for  the  most  part  in  solu- 
tion. This  is  the  case  also  when  the  simple  primary  aromatic 
amines  are  condensed  with  formaldehyde  in  dilute  acid  solution, 
but  contrasts  with  the  behavior  of  the  secondary  amines,  the  ex- 
ochlormethyl-derivatives  of  which  are  precipitated  by  hydro- 
chloric acid,  though  soluble  in  water.75 

Isolation  of  the  compound  HO.C6H4.NH.CH2C1,  obtained  from 
HO.C6H4.NH2.HC1  and  formaldehyde,  was  undertaken  in  a 
number  of  experiments,  in  which  the  acidity  ranged  from  that  of 
the  p-amino-phenol  hydrochloride  itself  to  that  produced  by  ad- 
dition of  about  an  equal  volume  of  concentrated  hydrochloric  acid 
to  the  solution.  Sulphuric  and  acetic  acids  also  were  used.  The 
solid  product  of  such  condensations  was  in  general  scanty,  dark 
brown  in  color,  and  amorphous ;  it  frequently  separated  in  coher- 
ent and  glue-like  masses.  Only  at  the  higher  concentrations  of 
acid  was  there  a  reasonably  copious  separation  of  solid  material. 
Thus,  using  20  grams  of  p-aminophenol  hydrochloride  in  90  cc. 
of  water,  25  grams  of  38  per  cent  formaldehyde  (more  than  two 
equivalents),  and  95  cc.  of  concentrated  hydrochloric  acid,  and 
allowing  condensation  to  proceed  in  the  cold  overnight,  only  a 
small  amount  of  material  separated.  After  heating  for  some 
time  on  the  water-bath,  a  dark  brown  powder  and  some  lumps 
separated  on  chilling.  When  dried,  this  material  weighed  14 
grams,  a  yield  of  64  per  cent,  assuming  it  to  be  the  compound 
HO.C6H4.NH.CH2C1.  It  was  found  to  be  soluble  in  hot  water, 
from  which  it  separated  in  muddy  form  on  chilling,  though  with 
considerable  loss.  The  aqueous  solution  was  precipitated  by  the 
common  acids;  sodium  carbonate  solution  produced  a  flocculent 
precipitate;  the  material  dissolved  very  readily  in  caustic  soda. 
The  "recrystallized"  material  dried  to  a  rather  brittle,  resinous 

74  D.  R.  P.  96851,  97710,  122474. 

T5  Goldschmidt,  Chem.  Ztg.  1.  c.\  Id.,  26,  606  (1902);  D.  R.  P.  97710. 

20 


METHYI<ATION  OF  PARA-AMINOPHENOi, 

mass,  yielding  when  ground  a  chocolate-brown  powder.  It  re- 
sponded positively  for  chlorine  both  to  the  copper-wire  test,  and 
to  silver  nitrate  in  water  solution.  The  latter  may  be  taken  as 
an  indication  of  impurity.76  The  same  conclusion  was  reached 
by  analysis  for  nitrogen  (Kjeldahl),  7.9  per  cent  being  found, 
instead  of  8.9  per  cent  as  required  by  the  formula.  When  con- 
densation was  carried  out  in  larger  volumes,  and  with  less  acid 
present,  practically  no  precipitate  appeared.  In  all  these  con- 
densations the  liquid  became  deep  red  in  color. 

Reduction  of  such  solutions  with  zinc-dust,  or  with  tin,77  by 
sodium  amalgam  (keeping  the  solution  slightly  acid),  by  sodium 
hydrosulphite,  or  by  electrolysis  in  sulphuric  acid  solution,  yielded 
no  secondary  amine  separable  as  nitrosamine.  Similar  results 
were  obtained  using  the  isolated  condensation-product. 

Reduction  of  the  Bisulphite  Addition-product  of  Methylene- 

p-amino  phenol — 

The  additive  union  of  sulphurous  acid  and  its  salts  with  for- 
maldehyde condensation-products  of  the  aromatic  amines  was 
studied  by  Eibner.78  The  formation  of  the  compound 
HO.C6H4.NH.CH2.SO3Na,  or  (HO.C6H4.N:CH2)NaHSO3,  is 
the  subject  of  D.  R.  P.  68707 :  p-aminophenol  is  condensed  with 
formaldehyde  in  alkaline  solution,  the  product  is  precipitated  by 
carbon  dioxide,  dissolved  promptly  in  sodium  bisulphite  solution, 
and  the  addition-product  obtained  by  crystallization.  The  bisul- 
phite compound  is  very  soluble  in  water,  and  crystallizes  as  small 
nearly  white  plates.  This  compound  can  be  very  conveniently 
prepared  by  addition  of  solid  p-aminophenol  to  a  hot  concentrated 
solution  of  formaldehyde  bisulphite.  The  base  passes  into  solu- 
tion; when  chilled,  the  liquid  sets  to  a  mass  of  crystals.  A 
fairly  strong  solution  of  this  product,  when  acidified  with  sul- 
phuric or  hydrochloric  acid,  separated  small  glistening  crystals, 
much  less  soluble  in  water  than  the  original  compound,  but  readily 
soluble  in  alkali.  Hot  dilute  sulphuric  acid  liberated  sulphur 
dioxide;  the  odor  of  formaldehyde  was  noticed  also.  It  seems 
T«  D.  R.  P.  96851. 

"  Goldschmidt,  Chem.  Ztg.  28,  1229  (1904). 
78  Annal.,  316,  89  (1901). 

21 


MSTHYI.ATION  OF  PARA-AMINOPHENOI, 

that  this  compound  is  the  free  acid  HO.C6H4.NH.CH2.SO3H. 
Eibner79  reported  an  analogous  behavior  of  the  corresponding 
aniline  compound. 

Efforts  to  convert  the  compound  HO.C6H4.NH.CH2.SO3Na 
into  HO.C6H4.NH.CH3  were  referred  to  on  page  18. 

Hydrogenation  of  N-Methylene-p-aminophenol,  (HO.C6H4.N:CH2)n 

Experiments  included  under  the  above  heading  constitute  the 
chief  experimental  basis  of  this  paper,  and  will  be  described  with 
more  detail  than  was  thought  desirable  for  other  methods.  The 
principal  operations  in  all  of  the  methods  to  be  described  are 

(1)  Condensation  of  p-aminophenol  and  formaldehyde  in  al- 
kaline solution. 

(2)  Reduction  of  the  condensation-product. 

(3)  Isolation  of  the  methylated  base 

(i)  Condensation  of  p-Aminophenol  and  Formaldehyde  in 
Alkaline  Solution— 

According  to  the  directions  of  D.  R.  P.  68707,  p-aminophenol 
is  dissolved  in  water  (21  grams  per  liter),  the  solution  filtered, 
chilled  to  5° — io,°  and  treated  with  somewhat  more  than  one 
equivalent  each  of  sodium  hydroxide  and  formaldehyde.  The 
solution  is  allowed  to  stand  several  hours,  and  the  condensation- 
product,  present  in  solution  as  the  phenolate,  is  precipitated  by 
conducting  carbon  dioxide  into  the  liquid,  or  by  addition  of  soda. 
The  liquid  always  possesses  a  strong  and  offensive  "fishy"  odor, 
and  darkens  promptly  when  exposed  to  air.  The  precipitated 
methylene-base  is  generally  flocculent,  and  light  in  color,  with 
often  a  pinkish  cast.  If  incorrectly  precipitated,  it  may  appear 
in  the  form  of  large  coherent  lumps. 

The  condensation-product  is  insoluble  in  water,  ether,  or  ben- 
zene; it  is  soluble  in  alcohol,  readily  soluble  in  alkali,  the  solu- 
tion thus  obtained  having  the  properties,  as  regards  odor  and 
air-oxidation,  of  the  original  condensation-liquid;  the  alkaline 
solution  reduces  silver  salts.  The  condensation-product  is  pre- 
cipitated from  alkaline  solution  by  addition  of  acids,  but  the 
79  /.  c. 


22 


METHYLATION  OF  PARA-AMINOPHENOI, 

precipitate  dissolves  in  a  sufficient  excess  of  the  acid:  the  odor 
of  formaldehyde  can  then  be  detected,  indicating  hydrolysis  of 
the  methylene-base.  When  dried  in  air,  methylene-p-aminophenol 
darkens  somewhat,  as  a  result  of  polymerization,  and  probably 
of  oxidation. 

It  was  found  convenient  to  use  p-aminophenol  hydrochloride 
instead  of  the  free  base,  because  of  the  greater  stability  and  solu- 
bility of  the  former.  Most  of  the  material  used  was  the  East- 
man product.  It  contained  1.39  per  cent  of  inorganic  material 
(ash),  and  0.12  per  cent  moisture.  Early  experiments  were  made 
using  Kahlbaum's  p-amino-phenol  hydrochloride,  and  some  others 
using  material  prepared  electrolytically  by  Dr.  H.  S.  Lukens. 

For  the  purification  of  p-aminophenol  hydrochloride  advantage 
was  taken  of  the  fact  that  this  salt  is  precipitated  almost  com- 
pletely when  its  strong  solution,  externally  cooled,  is  saturated 
with  gaseous  hydrochloric  acid.  To  obtain  the  free  base  for  im- 
mediate use,  a  concentrated  solution  of  the  hydrochloride,  cooled 
to  about  o°,  was  treated  with  strong  sodium  carbonate  solution 
until  effervescence  ceased.  The  base  separated  in  granular  form, 
and  was  filtered  off  and  pressed.  The  yield  by  this  method  is 
good,  the  solubility  of  the  base  at  o°  being  about  I  part  per  100 
of  water.  The  product  contains  alkali,  and  cannot  be  dried  or 
kept.  To  prepare  p-aminophenol  in  stable  form,  it  is  advisable  to 
crystallize  it  from  hot  water  containing  bisulphite,  and  to  wash  it 
with  cold  bisulphite  solution. 

To  study  the  condensation  quantitatively,  the  methylene-base, 
after  formation  under  the  selected  conditions,  was  precipitated 
from  the  properly  diluted  solution,  washed  with  water,  dried  care- 
fully, and  weighed.  The  procedure  for  the  isolation  is  given  later. 
In  some  of  the  later  experiments  the  uncondensed  p-aminophenol 
was  precipitated  from  the  filtrate  in  the  form  of  its  benzylidine- 
derivative.  The  latter  is  precipitated80  by  shaking  the  solution, 
acidified  with  acetic  acid,  with  benzaldehyde.  The  product  is 
washed  with  water,  dried,  and  weighed. 

The  results  obtained  under  various  conditions  of  condensation 
appear  in  Table  I. 

10  Haegele,  Ber.,  25,  2753  (1892);  Cf.  Michaelis,  Per.,  27,  3005  (1894) 

23 


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METHYtATlON  OF  PARA-AMINOPHENOI, 

The  data  just  given  seem  to  justify  the  following  conclusions : 

(1)  The  extent  of  the  condensation  is  relatively  independent 
of  experimental  conditions,  provided  that  there  are  present  at  least 
one  equivalent  of  formaldehyde,  and  two  equivalents  of  sodium 
hydroxide,  for  each  equivalent  of  p-aminophenol  hydrochloride 
(or  one  equivalent  of  sodium  hydroxide  if  free  p-aminophenol 
is  used).     Excess  of  formaldehyde  or  of  sodium  hydroxide  is 
without  apparent  effect. 

(2)  Low  temperature  favors  slightly  increased  condensation, 
as  shown  by  the  sixth,  seventh,  and  ninth  experiments,  in  com- 
parison with  other  trials,  which  were  conducted  at  15° — 20.° 

(3)  Condensation  is  not   increased  by  prolongation   of  the 
time  beyond  two  hours.     As  shown  by  experiments  not  listed 
above,  over-night  condensations  tend  to  yield  a  denser  and  darker 
product,  with  no  advantage  in  the  matter  of  yield  or  of  ease  of 
reduction. 

(4)  The  volume  in  which  condensation  occurs  is  almost  with- 
out effect.     The  only  definite  exception  to  this  statement  is  pre- 
sented by  the  thirteenth  experiment,  in  which  the  volume  was 
relatively  large,  the  result  being  that  normal  condensation  was 
not  quite  complete  at  the  end  of  two  hours. 

(5)  The  last  four  experiments  indicate  that  practically  all 
the  p-aminophenol  hydrochloride  taken  initially  is  accounted  for, 
either  as  methylene-p-aminophenol  or  as  the  uncondensed  base. 

(6)  Condensation  of  formaldehyde  and  p-aminophenol  occurs 
to  the  extent  of  about  75  to  85  per  cent. 

The  experiments  recorded  above,  together  with  many  inciden- 
tal observations  made  during  the  course  of  the  work,  led  to  the 
adoption  of  the  following 

Procedure  for  Condensation  of  Formaldehyde  and  p-Amino- 

phenol — 

(a)  Condensation — Dissolve  10  parts  of  p-aminophenol  hydro- 
chloride  in  about  60  parts  of  water,  and  filter  the  solution. 
Transfer  the  nitrate  to  a  flask,  and  chill  well  under  the  tap,  or 
better  in  ice.  Add  at  one  time  one-half  of  a  solution  which  con- 
tains 7.5  parts  (somewhat  more  than  two  equivalents)  of  sodium 


MET  HYI^ATION  OF  PARA-AMINOPH^NOI, 

hydroxide,  and  cool  until  the  heat  of  neutralization  is  absorbed. 
Now  add  the  remaining  sodium  hydroxide,  which  will  dissolve 
the  precipitated  p-aminophenol.  To  the  cold  alkaline  solution  add 
6  parts  of  38  per  cent  formaldehyde  (somewhat  more  than  one 
equivalent)  gradually,  with  rotation  of  the  flask.  Insert  a  stopper, 
and  keep  the  flask  in  a  cool  place  for  two  or  three  hours. 

(b)  Isolation — Pour  the  liquid  into  a  large  beaker  or  jar  con- 
taining cold  water,  and  provided  with  an  efficient  mechanical 
stirrer,  and,  appropriately  supported  above  the  precipitating 
vessel,  a  separatory  funnel  containing  30  per  cent  acetic  acid. 
The  volume  at  the  time  of  precipitation  should  be  rather  large, 
or  the  liquid  will  become  so  filled  with  the  precipitated  product  as 
to  interfere  with  effective  stirring.  A  volume  somewhat  greater 
than  500  cc.  is  convenient  for  precipitation  of  the  condensation- 
product  from  10-15  grams  of  p-aminophenol  hydrochloride.  With 
the  stirrer  in  motion,  allow  30  per  cent  acetic  acid  to  drop  into 
the  liquid,  until  the  reaction  is  distinctly  acid  to  litmus.  The 
condensation-product  will  be  precipitated  in  a  finely  granular 
form  which  settles  promptly  and  is  easily  filtered  and  washed. 
Filter  off  the  product  on  a  Biichner  funnel,  wash  with  cold  water, 
press  down  well  with  a  spatula,  and  dry  the  material  as  far  as 
possible  by  suction.  Transfer  it  to  a  watch-glass  or  plate,  and 
keep  in  a  slightly  warm  place  for  several  hours,  with  occasional 
reduction  of  lumps  as  drying  progresses.  Dry  finally  at  8o°-9O.° 
The  product  is  thus  obtained  as  a  loose,  soft,  grayish  powder, 
which  assumes  a  brown  color  after  long  exposure  to  the  air.  If 
the  drying  is  done  too  rapidly,  the  condensation-product  may 
become  resinous. 

Precipitation  by  carbon  dioxide  gives  equally  good  results,  but 
is  less  rapid  and  less  convenient;  the  use  of  sodium  bicarbonate 
solution  for  the  precipitation  occasionally  caused  the  separation 
of  a  coherent  product. 

When  reduction  of  the  methyl ene-p-aminophenol  is  intended, 
it  should  be  used  shortly  after  precipitation,  and  without  drying, 
as  the  completely  dried  product  is  reduced  with  difficulty.  As 
will  appear  below,  isolation  of  the  condensation-product  is  not 
essential,  and  is  quite  properly  omitted. 

26 


METHYLATION  OF  PARA-AMINOPH^NOIy 

Before  the  reduction  of  methylene-p-aminophenol  is  discussed, 
it  is  necessary  to  describe  the  methods  of  forming  and  handling 
the  nitrosamine  of  N-methyl-p-aminophenol,  since  it  is  in  this  form 
that  the  reduction-product  can  be  most  readily  and  completely 
isolated,  and  the  effectiveness  of  the  reduction  determined. 


p-Hydroxy-methylphenylnitrosamine, 

This  compound  is  obtained  by  the  usual  procedure  for  nitro- 
samine formation:  addition  of  sodium  nitrite  solution  to  the 
chilled  acidified  solution  of  the  secondary  amine.  It  separates 
from  solution  in  crystalline  form,  the  color  of  the  crystals  de- 
pending upon  the  presence  of  impurities  in  the  solution.  The 
pure  secondary  base  yields  nearly  white,  or  gray,  minute  needles, 
having  a  low  solubility  in  cold  water.  When  precipitation  is 
effected  from  solution  containing  p-aminophenol,  formation  of 
the  nitrosamine  is  noticeably  delayed,  due  no  doubt  to  the  superior 
reactivity  of  the  primary  base.  In  such  cases,  also,  tar-  formation 
is  almost  invariable,  and  the  nitrosamine  separates  as  brown 
granular  crystals.  Under  unfavorable  conditions  the  separation 
of  tar  has  been  considerable,  rendering  purification  of  the  nitro- 
samine, without  considerable  loss,  impossible. 

The  nitrosamine  is  a  somewhat  unstable  compound,  and  suf- 
fers serious  decomposition,  with  darkening,  if  an  attempt  is 
made  to  dry  it  while  moist  with  any  trace  of  the  acid  mother- 
liquor,  or  to  crystallize  it  from  strong  alcohol  ;  less  extensive  de- 
composition occurs  if  dilute  alcohol  is  used.  Rather  oddly,  the 
compound  seems  to  be  most  satisfactorily  crystallized  from  hot 
water,  in  which  it  is  moderately  soluble.  For  this  purpose,  the 
nitrosamine  is  suspended  in  water  (about  50  cc.  for  each  3 
grams),  the  mixture  heated  nearly  to  boiling,  and  about  5  cc.  of 
alcohol  added.  Solution  is  completed  without  unnecessary  heat- 
ing, and  the  liquid  is  cooled  in  ice.  The  nitrosamine  crystallizes 
out  rapidly,  and  with  nearly  quantitative  completeness. 

For  purposes  of  comparison,  2.0  grams  of  Metol  (Hauff)  were 
dissolved  in  200  cc.  of  water,  10  cc.  of  strong  hydrochloric  acid 
added,  and  the  solution  cooled  in  an  ice-bath.  It  was  then 
treated  dropwise  with  a  20  per  cent  solution  of  sodium  nitrite, 

27 


METHYLATION  OF  PARA-AMINOPHENOL 

until  a  drop  of  the  liquid,  applied  to  potassium  iodide  paper, 
showed  presence  of  nitrous  acid  in  excess.  The  nitrosamine 
separated,  during  the  addition  of  nitrite,  as  minute  almost  white 
needles,  which  were  filtered  off,  and  washed  sparingly  with  cold 
water.  After  several  recrystallizations  from  dilute  alcohol,  the 
nitrosamine  was  obtained  as  fairly  large  flat  needles,  slightly 
straw-tinged,  and  melting  at  134.3°  (corr.),  with  decomposition 
above  the  melting  temperature.  In  regard  to  the  melting-point 
of  the  nitrosamine,  it  should  be  added  that  Clarke81  gives  136°, 
a  value  never  obtained  by  the  writer. 

An  interesting  behavior  was  observed  when  an  excess  of 
nitrous  acid  was  allowed  to  act  upon  the  precipitated  nitrosamine. 
There  was  obtained  a  bright  yellow  insoluble  powder,  which 
melted  with  decomposition  at  I26°-I27°,  with  previous  softening. 
The  bottle  in  which  this  material  was  kept  was  gradually  colored 
a  bright  red  on  its  entire  inner  surface.  The  reaction  recalls  the 
simultaneous  nitrosation  and  nitration  of  methylaniline  by  means 
of  nitrogen  dioxide,  as  described  by  Stoermer.82 

Finally,  it  is  of  interest  to  consider  the  formation  of  the  nitro- 
samine as  an  identification  test  for  N-methyl-p-aminophenol. 
Attention  may  be  called  to  the  mercuric  acetate  test  described  by 
Harger83  which  is  said  to  disclose  the  presence  of  metol  in  a  con- 
centration of  i  :iooooo  by  the  gradual  development  of  a  grape- 
juice  color.  The  nitrosamine  test  is  by  no  means  so  delicate  as 
this,  but  is  more  characteristic.  It  appears  that  the  mercuric 
acetate  test  is  not  entirely  specific,  since  a  by-product  was 
obtained,  by  ether  extraction  of  the  alkalized  solution  after 
reduction  of  methylene-p-aminophenol,  which  was  obviously  not 
methyl-p-aminophenol  (its  sulphate  was  excessively  soluble  in 
water),  but  which  responded  to  the  mercuric  acetate  test  more 
strongly  than  "metol"  itself.  The  color  developed  was  nearly  blue, 
but  in  cases  of  doubt  would  certainly  cause  confusion. 

To  test  a  material  for  presence  of  a  salt  of  methyl-p-amino- 
phenol, a  little  of  the  substance  is  dissolved  in  a  small  volume  of 

81  /.  Ind.  Eng.  Chem.,  10,  891  (1918). 

82  Arr.,  31,2523  (1898). 

»/.  A.  C.  5.,  41,  270  (1919). 

28 


METHYLATION  OF  PARA-AMINOPHENOI, 

water,  the  solution  acidified  with  a  drop  or  two  of  hydrochloric 
acid,  chilled,  and  sodium  nitrite  solution  added  in  slight  excess. 
A  precipitate  of  minute  needles,  which  usually  appears  suddenly, 
and  which  seems  to  fill  the  liquid,  constitutes  a  positive  test.  If 
this  material  is  recrystallized  from  a  little  water  containing* 
alcohol,  and  its  melting-point  determined,  the  identification  of 
methyl-p-aminophenol  may  be  regarded  as  certain.  Identification 
by  means  of  the  sulphate  or  the  dibenzoyl-compound  is  less  con- 
venient, as  these  derivatives  are  less  characteristic  in  appearance, 
and  have  higher  melting-points. 

(2)     Reduction  of  N-Methylene-p-aminophenol  to  N-Methyl- 
p-aminophenol- 

Reference  to  page  15  shows  the  investigated  methods 
of  reduction  to  be  the  following: 

(a)  Reduction  by  Sodium  Amalgam,  or  Metallic  Sodium,  and 
Alcohol. 

(b)  Reduction  by  Zinc-dust  and  Alkali. 

(c)  Reduction  by  Zinc-dust  and  Acid. 

(d)  Reduction  Electrolytically  in  Alkaline  Solution. 

(e)  Reduction  Electrolytically  in  Acid  Solution. 

(f)  Reduction    Electrolytically    of    p-Nitrol-phenol     or    p- 
Nitroso-phenol  in  presence  of  Formaldehyde. 

(g)  Reduction  by  Hydrosulphite. 

In  all  cases  the  success  of  the  reduction  was  tested  by  means 
of  the  nitrosamine  reaction.  Of  the  above  methods,  only  method 
(c)  yielded  positive  results  which  were  uniformly  reproducible. 
Method  (e)  was  attended  with  some  success,  and  would  possibly 
repay  closer  study.  The  other  methods  were  apparently  quite 
unsuccessful,  and  may  be  disposed  of  rather  briefly. 

(a)  Reduction  by  Sodium  Amalgam,  or  by  Sodium,  and 
Absolute  Alcohol —  Both  aqueous  (acid  or  alkaline) 
solutions  of  the  condensation-product,  and  alcoholic  solutions, 
were  subjected  to  action  of  sodium  amalgam.  Reduction  by 
metallic  sodium  was  applied  to  the  solution  of  methlyene-p- 
aminophenol  in  anhydrous  ethyl  alcohol.  In  neither  case  could 


29 


METHYLATION  OF  PARA-AMINOPHENOI, 

presence  of  secondary  amine  be  detected  in  the  liquids,  after 
suitable  preparation  for  precipitation  of  nitrosamine. 

(b)  Reduction  by  Zinc-dust  and  Sodium  Hydroxide — 

This  method  was  applied  to  the  reduction  of  benzylidene- 
p-  aminophenol  and  of  methylene-p-aminophenol,  obtained  from 
p-aminophenol  by  condensation  with,  respectively,  benzaldehyde 
and  formaldehyde.  It  was  expected  that  these  compounds  would 
behave  similarly  upon  reduction;  their  chemical  similarity  is 
shown  by  the  formulas  HO.C6H4.N  :CH.C6H5  and 
HO.C6H4.N:CH2. 

Reduction  of  benzylidine-p-aminophenol84  was  quite  success- 
ful:  17  grams  of  this  compound  gave  18  grams  of  benzyl-p- 
aminophenol  hydrochloride,  a  yield  of  89  per  cent.  The  base  was 
found  to  melt  at  87°-88° ;  the  nitrosamine,  crystallized  from 
dilute  alcohol,  melted  at  142.5°  (corr.).  A  picrate  was  prepared, 
as  large  bright  yellow  irregular  prisms,  very  sparingly  soluble  in 
water,  and  melted  at  i66°-i67°  (corr.).  It  should  be  noted  that 
the  melting-point  of  the  nitrosamine  is  given85  as  148°. 

The  same  procedure,  as  well  as  that  of  A.  P.  1221077,  w^h 
varying  temperatures,  concentrations  of  alkali,  and  proportions 
of  base  and  formaldehyde,  when  applied  to  the  reduction  of 
methylene-p-aminophenol,  failed  to  produce  any  methyl-p-amino- 
phenol  which  could  be  separated  as  nitrosamine. 

(c)  Reduction  by  Zinc-dust  and  Acid — This  method  will  be 
discussed  in  some  detail  below. 

(d)  Reduction  Electrolytically  in  Alkaline  Medium — 

As  a  test  of  the  method,  the  benzylidine-p-aminophenol  obtained 
from  22  grams  of  p-aminophenol  hydrochloride  and  16  grams  of 
benzaldehyde  was  dissolved  in  12  per  cent  sodium  hydroxide 
solution,  and  subjected  to  reduction  using  iron  electrodes. 
Absorption  of  hydrogen  was  very  imperfect.  A  current  of  about 
5  amperes  (cathode  area  about  220  cm.2  was  continued  for  3.5 
hours,  with  continuous  evolution  of  unabsorbed  hydrogen.  The 
liquid  was  finally  acidified  with  sulphuric  acid,  filtered,  and 

84  D.  R.  P.  211869. 

85  Zeit.electroch.,  18,  745. 

30 


METHYLATION  OF  PARA-AMINOPHENOI, 


chilled,  when  2  grams  of  the  difficulty  soluble  benzyl-p-amino- 
phenol  sulphate  separated.  The  nitrosamine  of  this  product 
melted  at  142°  (see  page  30). 

The  same  procedure  was  applied  for  the  reduction  of  methy- 
lene-p-aminophenol  dissolved  in  15  per  cent  sodium  hydroxide 
solution.  There  was  no  apparent  absorption  of  hydrogen,  and  no 
methylated  product  was  detected  in  the  liquid  after  reduction. 
(e)  Reduction  Electrolytically  in  Acid  Solution  — 
The  electrolytic  cells  used  in  all  reductions  recorded  in  this 
paper  were  identical  in  design  with  the  cell  devised  by  Dr.  H.  S. 
Lukens,  whose  description  of  it  is  now  awaiting  publication. 
Cells  of  three  sizes  were  used,  having  capacities  of  500  cc.,  250 
cc.,  and  100  cc.  The  last  mentioned  was  used  for  reductions  cit 
lower  temperatures.  The  porous  cup  of  this  cell  was  closed  by 
a  large  rubber  stopper86  which  served  as  a  support  for  the  lead 
electrode,  the  liquid  seal  of  the  stirrer,  the  vent-tube,  and  an  in- 

TABLE  II. 

Electrolytic  Reductions 


Nitros- 

P.  A.  P. 

gms. 

Method  of  preparation 
for  electrolysis 

Amp. 

Volt 

Temp. 

Time 
hrs. 

Gas 

amine 
gms. 

f 

Yield 

12.5 

Condensed  overnight. 
Poured  into  equal 

10 

4 

- 

6 

None 
at  first 

I.O 

8 

vol.  40  £   H2SO4 

25 

Condensed  36  hours. 

5-5- 

4 



3 

H- 

+ 

Added  to  equal  vol. 

7 

after 

80  $  H2SO4 

i  hr. 

12.5 

Condensed  2  hours. 

2 

3-5 

£ 

3-5 

O.2 

1.6 

Ppted,  byCH3COOH; 
dissolved  in  45  gms. 

+ 
from 

25  <p  H2SO4,  added  40 
cc.  8056   H2SO4. 

start 

Small  cell 

12.5 

Condensed  overnight; 
ppted.  by  CO.>;  dis- 

2 

4 

5°- 
9° 

5 

+ 

2-4 

18 

solved  in  90  cc.  40  # 

after 

H2SO4  at  5°. 

ihr. 

Small  cell 

12.5 

Condensed  2  hours; 
ppted.  by  CH3COOH; 
dissolved  in  200  cc. 

IO-II 

6-7 

not 
cooled 

4 

little 
for 
i  hr 

I.O 

8 

20  £   alcoholic  H2SO4 

then  + 

86  Tafel,  Ber.t  33,  2209  (1900.) 


METHYIvATlON  OF  PARA-AMINOPHENOL 

serted  thermometer.  The  electrodes  of  these  cells  were  made  of 
commercial  lead. 

Results  of  some  of  the  electrolytic  reductions  are  tabulated 
above.  The  temperature,  during  addition  of  acid  to  condensa- 
tion-product (either  isolated  or  in  solution)  was  kept  low87  so 
as  to  avoid  hydrolysis  of  the  condensation-product. 

A  number  of  experiments  not  listed  above  were  entirely  with- 
out positive  result.  The  effect  of  amalgamating  the  cathode,  or 
of  using  very  pure  lead,  was  not  investigated.  In  the  last  ex- 
periment, an  aliquot  portion  was  examined,  after  reduction,  for 
unchanged  p-aminophenol :  37.5  per  cent  of  that  initially  taken 
was  recovered. 

(f)  Electrolytic  Reduction  of  p-Nitrophenol  or  of  p-Nitroso- 
phenol  in  Presence  of  Formaldehyde — 

Reference  may  be  made  to  the  statements  which  appear  under 
the  same  heading  on  page  17. 

The  reduction  of  15  grams  of  p-nitrophenol  in  alcohol-hydro- 
chloric acid  solution,  in  presence  of  10  grams  of  38  per  cent  for- 
maldehyde (about  one  equivalent),  absorbed  the  hydrogen  from 
a  current  of  10  amperes  for  over  an  hour.  Electrolysis  was  con- 
tinued for  nearly  five  hours,  when  evolution  of  unabsorbed  gas 
was  rapid.  The  clear  red  liquid  was  distilled  free  from  alcohol, 
made  alkaline  with  sodium  carbonate,  filtered,  and  extracted  with 
ether.  During  distillation  of  the  ether,  a  quantity  of  small 
crystalline  plates  separated.  These  were  removed  (1.4  gram), 
and  were  identified  as  p-aminophenol  [m.  p.,  i83°-i85°;  m.  p.  of 
benzylidine-derivative,  185°].  The  solid  material  precipitated 
by  sodium  carbonate  was  dissolved  in  dilute  hydrochloric  acid, 
boiled  with  charcoal,  filtered,  and  the  solution  precipitated  by 
sodium  acetate.  A  white  amorphous  material,  weighing  2.2 
grams,  was  obtained.  This  product  seems  to  correspond  to  the 
by-product  obtained  by  Lob  and  by  Goecke  during  the  electro- 
lytic reduction  of  p-nitrotoluene  in  presence  of  formaldehyde, 
and  is  possibly  an  anhydroamino-oxy-benzyl  alcohol. 

The  oil  left  after  evaporation  of  the  ether  was  subjected  to 
vacuum  distillation.  At  18  mm.,  distillation  began  at  162°,  and 
87  D.  R.  P.  143197- 

32 


METHYI^TION  OF  PARA-AMINOPHENOI, 

was  continued  up  to  175°  (25  mm.).  The  product  was  a  dark 
brown,  viscous  oil,  which  could  not  be  solidified ;  its  amount  was 
too  small  to  warrant  purification.  The  data  from  the  distilla- 
tion furnish  some  basis  for  the  belief  that  dimethyl-p-amino- 
phenol  (b.  p.30  =  162°)  was  present. 

A  number  of  similar  reductions  of  p-nitro-phenol  and  of 
p-nitrosophenol  were  carried  out  in  presence  of  formaldehyde, 
but  in  no  case  could  any  secondary  base  be  isolated  after  re- 
duction. This  method  seems  to  serve  only  for  the  formation  of 
dimethylanilines  from  the  corresponding  nitro-  or  nitroso-com- 
pounds ;  mono-methylation  apparently  does  not  occur. 

(g)     Reduction  by  Sodium  Hydro  sulphite- 
No  addition  need  be  made  to  the  remark  on  page  17. 

(c)  Reduction  of  N-Methylene-p-aminophenol  to  N-Methyl-p- 

aminophenol  by  Zinc-dust  and  Acid- 
After  a  number  of  preliminary  trials,  evidence  of  methylation, 
by  zinc-dust  and  dilute  hydrochloric  acid,  was  first  obtained  by 
isolation  of  a  benzoyl-compound  melting  at  172°- 177°  (m.  p. 
dibenzoyl-methyl-p-aminophenol  =  174°)-  By  a  similar  pro- 
cedure, using  sulphuric  acid,  a  nitrosamine  melting  at  I33°-I34° 
was  obtained,  identical  with  that  from  metol.  It  was  found  that 
reduction  by  zinc  and  acid  could  be  effected  either  with  or  with- 
out isolation  of  the  condensation-  product  HO.C6H4.N  :CH2.  The 
yields  were  always  small,  however,  a  fact  at  first  attributed  to 
the  decomposition  of  the  methylene-p-aminophenol  by  hydrolysis. 
Data  to  be  given  later  will  show  that  this  hydrolysis  is  by  no 
means  so  considerable  as  was  thought. 

The  conditions  by  variation  of  which  the  reduction  might  be 
expected  to  be  influenced  are  rather  numerous;  experiment  has 
shown,  however,  that  the  process  is  actually  rather  unresponsive 
to  modifications  in  conditions.  The  opinion  is  held  at  present 
that  the  small  extent  of  the  methylation  is  due  in  large  part  to 
a  side-reaction  of  the  same  kind  as  that  which  diminished  to  about 
40  per  cent  the  yields  in  Lob's  and  in  Goecke's  electrolytic  reduc- 
tions referred  to  previously.  There  seems  to  be  reason  to  be- 

33 


METHYI,ATION  OF  PARA-AMINOPHEJNOL 

lieve  that  this  side-reaction  is  only  the  normal  action  of  acid 
upon  the  formaldehyde  condensation-product,  as  shown  on  page 
8. 

Results  of  a  number  of  experiments  will  now  be  tabulated, 
showing  the  influence  of  various  conditions  upon  the  reduction. 
It  is  to  be  emphasized  that  the  yields  set  down  in  Tables  III,  IV, 
and  V,  neglect  the  recoverable  p-aminophenol  present  after  re- 
duction, and  are  calculated  on  the  basis  of  total  p-aminophenol 
taken  initially  and  that  finally  obtained  in  the  methylated  form 
(as  nitrosamine).  These  yields  are  therefore  given  too  low  by 
about  10  per  cent. 

TABLE  III. 

Experiments  to  determine 

(a)  Relative  values  of  several  methods  for  precipitating 
condensation-product. 

(b)  Necessity  for  isolation  of  condensation-product. 


P.  A.  P. 

gms. 

Preparation  for  reduction 

Temp, 
of 
reduc- 
tion. 

Nitros- 
amine 
gms. 

Yield 

Remarks 

"•5 

Condensed    over-night.      Ppted.  by 
CO2  ;  dissolved  in  40  ft  H2SO4  at  5°. 

in 
ice 

3-5 

27 

Precip- 
itation 
by  CO, 

10 

Condensed    2    hrs.      Pptd.  by    CO2; 
dissolved  in  40  $  H2SO4  at  i°. 

5°-8° 

2.a 

21 

10 

Pptd.  by  CO2;  diss.  4056  H2SO4at-2°. 

-2  to  +8° 

2.2 

21 

12-5 

Pptd.  CH3COOH;  diss.  50  £  H2SO4(ice) 

in  ice 

2.9 

22 

Pptation. 
CH3COOH 

IO 

Pptd.  CH3COOH;  diss.  40  0  H2SO4,-2°. 

-2  to  +8° 

2.1 

20 

20 

Pptd.  NaHCO3  (large  lump);  diss. 
in  40$  H2SO4  at  o°. 

c-6° 

4-0 

19 

NaHC03 

10 

Not    isolated;   sol.  added    to   equal 
vol.  (190  cc.)  4o$H3SO4at  15°. 

J5°- 
33° 

2.2 

21 

Not 
isolated; 
not 
cooled. 

IO 

Not  isolated;   sol.   added  to    equal 
vol.  (130  cc.)  40  <jt,  H2SO4  at  17°. 

I7o_ 
37° 

2.7 

26 

The  data  in  Table  III  indicate  that 

(a)  The  condensation-product  may  be  precipitated   equally 
well  by  carbon  dioxide  or  acetic  acid,  but  less  advantageously 
by  sodium  bicarbonate. 

(b)  No  advantage  is  gained  by  isolation  of  the  condensation- 
product.     It  is  indicated   also   that  low   temperatures   are   not 
essential  (see  Tables  IV  and  V). 


34 


METHYLATION  OF  PARA-AMINOPHENOL 
TABLE  IV. 

Experiments  to  determine 

(a)  Effect  of  variation  in  concentration  of  acid. 

(b)  Effect    of   variation    in   volume    in   which    reduction 
occurs. 

(c)  Necessity  for  cooling  before  and  during  reduction. 


P.  A.  P. 

gms. 

Preparation 
for 
Reduction 

Temp. 
of 
Reduc- 
tion 

Nitros- 
amine 
gms. 

* 

Yield 

Remarks 

10 

Pptd.  by  CH3COOH;  dissolved  in 
25%  H,S04at4° 

low 

1.8 

17 

25  j  H2S04 

10 

Pptd.  by  CH,COOH;  dissolved  in 
40  #  H2SO4  at-2° 

-2°  to 
+  8° 

2.1 

20 

40*   H2S04 

10 

Pptd.  by  CH3COOH;  dissolved  in 
50*  H2S04  at  4° 

low 

i-9 

18 

50  +  H2S04 

10 

Pptd.  by  CO*;  dissolved  in  190  cc. 
40  *  H2S04at-5° 

2° 

1.6 

15 

IO 

Pptd.  by  CH3COOH;  dissolved  in 
50  cc.  40  <£  H2SO4  at  -5° 

-i° 

2.1 

20 

IO 

Pptd.  by  CH3COOH;  dissolved  in 
loo  cc.  40  #  H2SO4,-8°  to  -2° 

-2°  to 
+  28° 

2.2 

21 

Effect 
of 
temp, 
variations 

IO 

Pptd.  by  COo;  dissolved  in  40  # 
H2SO4  at  5° 

o°to 
+  5° 

2-5 

24 

10 

Not  isolated;  equal  volume  (190  cc.) 
40*  H2SO4  added,  15° 

'5°- 
33° 

2.2 

21 

IO 

Not  isolated;  equal  volume  (130  cc.  'I 
40  ^  H2SO4  added,  17° 

I7°- 
32° 

2.7 

26 

The  above  experiments  show  that 

(a)  No  decided  effect  is  caused  by  variations  in  the  initial 
concentration  of  sulphuric  acid. 

(b)  Somewhat  better  results  are  obtained  when  the  volume 
is  restricted  (see  Table  V). 

(c)  No  advantage  is  gained  by  working  at  low  tempera- 
tures. 

In  subsequent  experiments  the  condensation-product  was  not 
isolated.  The  condensation  liquid  was  transferred  to  a  beaker, 
provided  with  a  mechanical  stirrer,  some  zinc-dust  was  added,  and 
an  excess  of  40  per  cent  sulphuric  acid  was  introduced.  While 
stirring  actively,  zinc-dust  was  added  so  as  to  maintain  it  in  ex- 
cess. In  several  experiments,  the  condensation  liquid  was  added 


35 


METHYLATION  OF  PARA-AMINOPHENOIv 


slowly  to  an  excess  of  acid  and  zinc-dust, 
experiments  are  shown  in  Table  V. 


Results  of  further 


which     reduction 


TABLE  V. 
Experiments  to  determine 

(a)  Effect  of  reduction  at  higher  temperatures 

(b)  Effect  of  variations  of  volume  in 
occurs. 

(c)  Effect  of  gradual  addition  of  condensation  liquid  to 
sulphuric  acid  and  zinc-dust. 

(Reduction  of  methylene-p-aminophenol  without  isolation.) 


P.  A.  P. 
gms. 

Preparation  for  reduction 

Temp, 
of 
reduc- 
tion. 

Nitros- 
amine 
gms. 

Yield 

Remarks 

10 

Added  equal  volume  (70  cc.)  of  40  $ 
H2S04. 

I5°-,° 

2.2 

21 

Average 
temp.       5° 

10 

Added  125  cc.  40$  H2SO4  to  solution 
diluted  to  400  cc. 

*5°V 

3-3 

31 

35° 

10 

Added  equal  volume  (70  cc.)  of  40$ 
H2S04. 

50°- 
28° 

3-3 

31 

40° 

10 

Added  equal  volume  (120  cc.)  of  40$ 
H2SO4. 

30°- 
86° 

3-6 

34 

"  60°-80° 

10 

Added  equal  volume  (loocc.)  of  40$ 
H2SO4. 

7o°- 
90° 

3-3 

31 

90° 

10 

Added  equal  volume  (100  cc.)  of  40$ 
H2S04. 

65°- 
103° 

3-2 

30.5 

"        100° 

10 

Added  equal  volume  (65  cc.)  of  40$ 
H2S04. 

6o°- 
90° 

2-5 

24 

Reduction  in 
small  vol. 

10 

Solution  added  dropwise  to  equal 
volume  (116  cc.)  of  40$  H2SO4 
containing  zinc-dust:  25  gms. 
zinc  in  all. 

20°- 

49° 

2-5 

24 

Condensa- 
tion liquid 
added  to 
zinc  and 
H2S04 

10 

Same  as  above;  volume  =  65  cc. 
Added  rapidly  to  zinc  and  H2SO4. 

6o°- 
80° 

2.6 

25 

10 

Same  as  above;  volume  =  100  cc. 
Higher  temperature. 

8o°- 
90° 

3-0 

29 

The  results  in  Table  V  justify  the  conclusions  that 

(a)  The  most  favorable  reduction  temperature  is  rather 
high,  lying  above  50°,  and  probably  at  70°  to  80°. 

(b)  Variations  in  the  volume  of  the  liquid  in  which  re- 
duction  is   effected    do    not    have   any   definite    effect 
upon  the  results.     Smaller  volumes  are  preferable  for 
reasons  of  convenience. 


METHYLATION  OF  PARA-AMINOPHSNOI, 

(c)  No  improvement  is  caused  by  gradual  addition  of  the 
condensation  liquid  to  sulphuric  acid  in  which  zinc- 
dust  is  kept  in  excess,  to  avoid  prolonged  contact  of 
acid  and  condensation-product  before  the  latter  can 
be  reduced. 

Miscellaneous  Experiments — 
Reduction  of  Dried  Condensation-product — 
Eighteen  grams  of  dried  methylene-p-aminophenol  were  dis- 
solved in  150  cc.  of  40  per  cent  sulphuric  acid,  and  reduced  with 
15  grams  of  zinc-dust  at  o°  to  5°.    There  was  obtained  2.2  grams 
of  nitrosamine,  corresponding  to  n.6  per  cent  reduction. 

In  another  experiment,  methylene-p-aminophenol  which  had 
become  resinous  on  drying  was  similarly  treated.  In  contact 
with  acid,  the  dark  red  powder  coagulated  into  a  single  glue-like 
mass,  which  remained  unattacked  upon  addition  of  zinc-dust. 

These  experiments  demonstrate  the  increased  difficulty  in  re- 
duction which  is  consequent  upon  drying  the  condensation-pro- 
duct, presumably  as  a  result  of  polymerization. 

Effect  of  Presence  of  Excess  Formaldehyde  added  to  Conden- 
sation-liquid previous  to  Acidification  and  Reduction — 
For  experimental  conditions,  see  last  experiment  in  Table  III. 
After  condensation,  10  grams  of  38  per  cent  formaldehyde  were 
added,  and  then  one  volume  of  40  per  cent  sulphuric  acid.    Re- 
duction was  carried  out  as  usual.     Addition  of  sodium  nitrite 
caused  brisk  effervescence,  but  no  nitrosamine  was  formed. 

The  prevention  of  hydrolysis  of  methylene-p-aminophenol  was 
therefore  not  achieved,  while  normal  reduction  was  in  some  way 
prevented,  by  presence  of  excess  formaldehyde  in  the  acid  solu- 
tion. 

From  the  preliminary  experiments,  the  results  of  which  are  re- 
corded above,  was  developed  the  procedure  used  in  succeeding 
experiments,  in  which  the  course  of  the  reaction  was  examined 
somewhat  more  closely. 

The  extent  to  which  p-aminophenol  escapes  condensation  with 
formaldehyde  is  shown  in  Table  I  (page  24).  The  p-aminophenol 

37 


METHYIvATlON  OF  PARA-AMINOPHENOI, 

present  after  reduction  includes  this,  in  addition  to  any  formed 
by  acid  hydrolysis  of  the  methylene-p-aminophenol. 

Recovery  of  unchanged  p-aminophenol  from  the  solution  after 
reduction  is  readily  effected  by  condensation  with  benzaldehyde.88 
For  this  purpose,  the  solution  is  nearly  neutralized  (left  slightly 
acid),  sodium  acetate  is  added,  and  the  liquid  is  shaken  with  a 
slight  excess  of  benzaldehyde.  The  benzylidine  p-aminophenol 
separates  as  light-colored  flocks  or  clumps,  which  adhere  to  the 
vessel  if  too  large  an  excess  of  benzaldehyde  is  present.  The 
precipitate,  when  completely  formed,  is  filtered  off,  and  washed 
with  water.  It  may  be  dried  and  weighed,  i.o  gram  correspond- 
ing to  0.73  gram  of  p-aminophenol  hydrochloride.  Benzylidine- 
p-aminophenol  is  readily  crystallized  from  dilute  alcohol  as  small 
pale  yellow  needles  which  melt  at  185°.  It  is  well  adapted  to  the 
identification  of  p-aminophenol. 

To  recover  p-aminophenol  and  benzaldehyde  from  benzylidine- 
p-umino  phenol,  advantage  was  taken  of  the  ready  hydrolysis  of 
the  last-named  by  strong  acids.  The  product  was  transferred  to 
a  distillation-flask,  water  added  to  make  a  paste,  about  an  equal 
weight  of  strong  hydrochloric  acid  added,  and  the  mixture  dis- 
tilled with  steam.  The  benzylidine-p-aminophenol  was  thus  de- 
composed, and  the  benzaldehyde  formed  passed  into  the  distillate. 
It  was  extracted  therefrom  by  ether,  and  recovered  by  distilla- 
tion. The  acid  liquid  from  the  decomposition  was  treated  so  as 
to  obtain  the  p-aminophenol  hydrochloride  ( see  page  23 ) .  Work- 
ing in  this  way,  there  was  obtained,  from  37  grams  of  benzylidine- 
p-aminophenol, 

17.8  grams  of  benzaldehyde  ( i78°-i85°)  90  per  cent. 

23.2  grams  of  p-aminophenol  hydrochloride          85.6  per  cent. 
Preparation  of  N -Methyl- p-aminophenol  from  its  Nitrosamine 

Among  the  methods  suggested  for  replacement  of  the  nitroso- 
group  by  hydrogen  may  be  mentioned 
88  D.  R.  P.  208434. 

38 


METHYIvATlON  OF  PARA-AMINOPHENOI, 

(a)  Reduction  by  tin,  zinc,  or  iron,  and  acid.89    It  will  be 
recalled  that  by  milder  reduction,  hydrazine  deriva- 
tives are  formed.90 

(b)  Action  of  strong  hydrochloric  acid,  or  gaseous  HC1.91 

(c)  Heating  with  aniline.92 

Several  attempts  to  convert  p-oxy-phenylmethylnitrosamine  to 
the  secondary  base,  by  action  of  hydrochloric  or  sulphuric  acid, 
resulted  unsuccessfully.  Decomposition  occurred  readily,  with 
evolution  of  nitrogen  oxides,  but  the  decomposition  was  accom- 
panied by  considerable  tar- formation,  so  that  only  small  amounts 
of  crystalline  product  could  be  isolated  from  the  black  and  vis- 
cous liquid. 

Reduction  of  the  nitrosamine  with  zinc  and  hydrochloric  acid 
was  more  successful,  and  was  conducted  thus:  10  grams  of 
nitrosamine  was  suspended  in  water  with  20  grams  of  zinc-dust. 
While  stirring  (mechanically),  75  cc.  of  strong  hydrochloric  acid 
was  added  from  a  separatory  funnel,  at  such  a  rate  that  the  tem- 
perature did  not  exceed  50°.  When  action  was  at  an  end,  the 
liquid  was  treated  with  ammonium  chloride,  made  alkaline  with 
ammonia  (using  enough  to  hold  the  zinc  in  solution),  and  ex- 
tracted with  ether.  The  residue  from  the  evaporation  of  the 
ether  was  taken  up  in  a  little  dilute  sulphuric  acid,  the  liquid 
digested  with  animal  charcoal,  and  crystallized.  There  were  ob- 
tained 4.2  grams  of  the  sulphate,  corresponding  to  37  per  cent. 
As  several  trials  resulted  no  better  than  this,  it  was  decided  to 
isolate  the  methylated  base  as  such,  without  intermediate  for- 
mation of  the  nitrosamine. 

Procedure  for  Methylation  of  p-Amino phenol,  with  Final  Ex- 
perimental Results — 

Condensation — This  operation  was  conducted  as  described  on 
page  25,  paragraph  (a). 

Reduction — Transfer  the  solution  to  a  beaker,  into  which  is 
89Noelting  and  Boasson,  Ber.,  10,  795  (1877);  Weyl,  "Methoden",  I, 
219  (1911). 

90  Weyl,  /.  c.\  Backer,  Rev.  trav.  chim.,  32,  39. 

91  Geuther,  AnnaL,  128,  151  (1863);  Stoermer,  Ber.,  31.  2523  (1898). 
91  Henriques,  Ber.y  17,  2671  (1884). 

39 


METHYIvATlON  OF  PARA-AMINOPHENOI, 

suspended  a  mechanically  operated  stirrer,  and  a  thermometer; 
the  beaker  is  supported  on  a  plate  above  a  bunsen  burner.  Weigh 
out  i  to  1.5  times  as  much  zinc-dust  as  was  taken  of  p-amino- 
phenol,  and  introduce  a  portion  of  it  into  the  beaker.  Warm  to 
about  50°  a  volume  of  40-50  per  cent  sulphuric  acid  equal  to 
that  of  the  condensation  liquid,  and  add  it  all  at  one  time.  While 
keeping  the  stirrer  in  rapid  motion,  add  the  zinc  steadily  and  in 
small  portions  with  sufficient  rapidity  that  the  solution  is  con- 
tinually filled  with  gas-bubbles.  Raise  the  temperature  as  quickly 
as  possible  to  7O°-8o° ;  this  is  much  assisted  by  adding  the  zinc 
in  larger  portions  at  first.  Keep  the  temperature  near  80°  by 
application  of  heat,  until  all  the  zinc  has  been  added,  and  has 
dissolved.  The  liquid  will  be  entirely  clear  and  colorless,  except 
for  a  small  amount  of  insoluble  matter  from  the  zinc. 

Removal  of  Unaltered  p-Aminophenol — 

Almost  neutralize  the  liquid  with  sodium  hydroxide,  add 
sodium  acetate,  transfer  to  a  capacious  Erlenmeyer  flask,  and 
cool.  Add  a  slight  excess  of  benzaldehyde  (3  or  4  grams  for 
each  10  grams  of  p-aminophenol  hydrochloride  taken  initially 
should  be  ample),  and  shake  the  stoppered  flask.  After  the 
benzylidine-p-aminophenol  has  separated,  filter  it  off,  and  wash 
with  water.  It  may  be  treated  as  outlined  on  page  38  for  recovery 
of  benzaldehyde  and  p-aminophenol  hydrochloride. 

Isolation  of  N-Methyl-p-ammophenol  as  Sulphate — 
Transfer  the  filtrate  to  a  distillation-flask,  and  distil  in  steam 
until  all  excess  of  benzaldehyde  is  removed.  Concentrate  the 
liquid  nearly  to  separation  of  salts,  cool,  add  ammonium  chloride, 
and  then  strong  ammonia  until  the  precipitated  zinc  redissolves. 
Extract  the  alkaline  liquid  four  or  five  times  with  ether,  which  is 
then  distilled  off.  Take  up  the  residue  in  enough  40  per  cent 
sulphuric  acid  to  establish  distinct  acidity,  and  cool  the  liquid 
strongly.  It  should  set  to  a  stiff  magma  containing  crystals  of 
the  sulphate.  Filter,  and  wash  the  crystals  with  alcohol.  Con- 
centrate the  filtrate  to  obtain  a  further  crop  of  the  sulphate. 
Digestion  with  good  animal  charcoal  will  assist  the  crystallization 
by  elimination  of  tarry  material.  These  crystallizations  may 

40 


METHYIvATlON  OF  PARA-AMINOPHENOI, 

cause  some  trouble,  due  to  the  rather  viscous  nature  of  the  liquid, 
and  to  the  presence  of  impurities  which  appear  to  retard  crystal- 
formation. 

Additional  solid  material  may  be  obtained  from  the  final 
mother-liquor  by  evaporation  to  pastiness,  and  extraction  with 
alcohol.  A  light  gray  powder  is  thus  obtained  (as  a  residue  in- 
soluble in  alcohol),  which  contains  some  methyl-p-aminophenol 
sulphate,  but  is  evidently  composed  largely  of  some  other  sub- 
stance, which  is  very  soluble  in  water.  This  material  has  usually 
given  the  nitrosamine  reaction,  and  with  mercuric  acetate  de- 
veloped a  strong  blue  color  (see  page  28).  It  cannot  easily 
be  crystallized,  because  of  its  high  solubility.  Benzoylation  of 
some  of  this  substance  yielded  a  product  which  melted  at  132°- 
134°.  Recrystallization  of  the  main  product  affords  a  separation 
of  the  methyl-p-aminophenol  sulphate  from  the  more  soluble 
compound.  The  mother  liquors,  however,  always  contain  very 
appreciable  quantities  of  the  former,  as  may  be  demonstrated  by 
precipitation  as  nitrosamine. 

The  ether  extraction  was  a  rather  troublesome  operation.  The 
quantity  of  ammonia  required  to  hold  the  zinc  in  solution  ren- 
ders the  liquid  somewhat  bulky  for  hand-extraction ;  a  mechanical 
shaker,  or  the  continuous  extraction  device  of  Schwarz93  would 
be  of  great  assistance.  During  the  extractions,  there  was  a 
continual  separation  of  a  black  foam-like  material,  which  ap- 
peared to  fill  the  ether  layer  completely ;  this  was  filtered  off  from 
time  to  time.  The  ether  extracts  were  bright  red  in  color.  The 
complete  removal  of  the  coloring-matter  requires  many  extrac- 
tions, and  is  thought  to  be  unnecessary,  as  methyl-p-aminophenol 
is  very  soluble  in  ether. 

In  the  experiments  tabulated  below,  aliquot  portions  were  in 
most  cases  examined  for  uncondensed  p-aminophenol  after  the 
condensation,  and  again  after  reduction;  the  extent  of  the  re- 
duction was  determined  by  nitrosamine  precipitation  in  another 
aliquot  portion.  The  indicated  yields  are  calculated  on  the  basis 
of  the  weight  of  p-aminophenol  hydrochloride  actually  subjected 

n  Ber.,  17,  Ref.  402    (1884);  Weyl,  "Methoden",  General  Part,  p.   131 
(1909).  p.  515  (1921). 

41 


METHYLATION  OF  PARA-AMINOPHENOL 

to  methylation,  and  not  recoverable  (compare  Tables  III,  IV,  V). 
The  main  portion  of  each  experiment  was  treated  for  separation 
of  the  methylated  base  in  the  form  of  its  sulphate.  Freed  from 
detailed  data,  and  expressed  only  in  nearest  percentages,  the  re- 
sults of  the  final  experiments  are  as  shown  in  Table  VI. 

TABLE  VI. 


Yield  of 
cond. 
prod. 

recovered 
after 
cond. 

recovered 
after 
reduction 

produced 
by  by-       . 
drolysis 

Yield 
based  on 
nitros- 
amine 

Yield 
based  on 
sulphate 

P.  A.  P. 
acctd.  for 

% 
P.  A.  P. 
not 
acctd.  for 

— 

- 

26 

- 

36 

- 

- 

- 

— 

- 

35 

- 

47 

23 

66 

34 

6? 

29 

40 

11 

47 

37 

68 

32 

77 

21 

32 

11 

39 

28 

59 

41 

77 

21 

,     25 

4 

30 

31 

48 

52 

- 

- 

33 

-  ' 

- 

28 

52 

48 

From  these  results  it  may  be  concluded  that 

(a)  About  one- fourth  of  the  p-aminophenol  taken  escapes 
condensation  with  formaldehyde. 

(b)  Hydrolysis  of  the  condensation-product   during   reduc- 
tion removes   from  the  reaction  an  additional   10  per  cent  of 
p-aminophenol. 

(c)  The  process  is  effective  in  methylating  about  40  per  cent 
of  the  p-aminophenol  brought  into  reaction,  as  determined  by 
precipitation  of  the  secondary  base  as  nitrosamine. 

(d)  The  yield  of  the  process,  in  terms  of  the  secondary  base 
itself,  isolated  as  its  sulphate,  and  referred  to  the  amount  of 
p-aminophenol  actually  subjected  to  methylation,  is  about  30  per 
cent.    The  method  of  isolation  is  insufficiently  perfected. 

(e)  Of  the  total  p-aminophenol  initially  taken,  about  60  per 
cent  can  be  accounted  for,  either  as  methylated  base,  or  as  un- 
changed p-aminophenol,  which  can  be  recovered  without  trouble. 

(f)  Approximately  40  per  cent  of  the  p-aminophenol  initially 
taken  enters  into  some  side-reaction,  and  has  not  been  accounted 
for. 


42 


•       •    t       •    •     •     *  o       • 

"•»"•*•••••••         '  •  *    fc      *    • 


METHYIvATlON  OF  PARA-AMINOPHENOI, 

Identification    of    N-M 'ethyl- p-amino phenol,     produced  from 
p-Aminophenol  by  the  Method  described  above — 

(1)  Nitrosamine  melted  at  133°  (corr.). 

(2)  Dibenzoyl-derivative  melted  at  174°  (corr.). 

(3)  Sulphate  (Metol)  charred  at  242°,  and  melted  at  257°. 

(4)  Nitrogen  Determination   (Kjeldahl)  : 

Found:       8.01 

7.84     Average=7.9% 

7-85 

Calculated  for 

(HO.C6H4.NH.CH3).2H,SO4: 

8.14% 

(5)  Sulphate  responded  strongly  to  mercuric  acetate  test. 

(6)  A  photographic  film  was  developed  by  a  solution  con- 
taining a  little  of  the  sulphate,  sodium  sulphite,  and 
sodium  carbonate. 

IV.     Summary 

(1)  The  available  methods  for  conversion  of  the  condensa- 
tion-products of  p-aminophenol  and  formaldehyde  into  N-methyl- 
p-aminophenol  have  been  reviewed,  and  applied  experimentally. 

(2)  The  reduction  of  N-methylene-p-aminophenol  (produced 
by  condensation  of  p-aminophenol  with  formaldehyde  in  alkaline 
solution)  by  zinc-dust  and  sulphuric  acid  has  in  particular  been 
subjected  to  investigation,  and  the  course  of  the  reaction  has 
been  studied. 

(3)  It  has  been  found  that  the  condensation  of  formaldehyde 
and  p-aminophenol  in  alkaline  solution  is  from  70  to  85  per  cent 
complete;  that  during  reduction  by  zinc  and  acid  a  further  10 
per  cent  of  the  initial  p-aminophenol  is  freed  by  hydrolysis  of 
the  condensation-product ;  that  about  40  per  cent  of  the  p-amino- 
phenol which  actually  enters  the  reaction  as  methylene-p-amino- 
phenol,  and  is  subjected  to  reduction,  is  methylated.     The  un- 
changed p-aminophenol  may  be  recovered  after  removal  from 
the  solution  as  benzylidine-p-aminophenol  after  the  reduction. 


43 


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